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Kang Q, Wu Y, Jiang K, Yao Q, Li J, Li Y, Tang N, Zhang X, Li Z. Acyl-CoA binding protein (ACBP) in Siberian sturgeon (Acipenser baerii Brandt): Characterization, synthesis and orexigenic function. Int J Biol Macromol 2025; 305:141280. [PMID: 39978502 DOI: 10.1016/j.ijbiomac.2025.141280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 11/12/2024] [Accepted: 02/17/2025] [Indexed: 02/22/2025]
Abstract
Acyl-CoA binding protein (ACBP) exhibits the activity of autophagy and lipid metabolism regulation in mammals, but its indispensable role in appetite regulation has received great attention in recent years. However, its feeding regulation function in fish is unclear. In this study, we cloned the acbp gene of Siberian Sturgeon (Abacbp) which possesses high homology with those of other vertebrate species and extremely high expression in duodenum and hypothalamus. Interestingly, Abacbp mRNA was significantly increased by short-term fasting but decreased after long-term fasting and recovered after refeeding, suggesting its latent ability in appetite regulation and compensatory growth (CG). Moreover, intraperitoneal injection of Siberian sturgeon ACBP protein (AbACBP) promoted food intake and the expressions of anorexigenic factors were down-regulated and the orexigenic factors were up-regulated. In addition, the specific receptor of ACBP regulating feeding has yet to be identified. Still, our present study found that peripheral AbACBP caused the upregulation of cb1r and the inhibition of the PI3K-AKT-mTOR-S6k signal pathway in the hypothalamus. In conclusion, the research first explored the appetite-stimulating function and mechanism of ACBP. It is of great value to construct the expression strain to produce the appetite-promoting protein ACBP in large quantities for promoting the appetite of farmed animals.
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Affiliation(s)
- Qin Kang
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu 611130, Sichuan, China
| | - Yuru Wu
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu 611130, Sichuan, China
| | - Kezhen Jiang
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu 611130, Sichuan, China
| | - Qin Yao
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu 611130, Sichuan, China
| | - Jiamei Li
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu 611130, Sichuan, China
| | - Yingzi Li
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu 611130, Sichuan, China
| | - Ni Tang
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu 611130, Sichuan, China.
| | - Xin Zhang
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu 611130, Sichuan, China.
| | - Zhiqiong Li
- Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, 211# Huimin Road, Chengdu 611130, Sichuan, China.
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Yuan M, Cao Z, Li Q, Liu R, Wang J, Xue W, Lyu Q. Fasting-induced miR-7a-5p in AgRP neurons regulates food intake. Metabolism 2024; 158:155959. [PMID: 38942170 DOI: 10.1016/j.metabol.2024.155959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 06/21/2024] [Accepted: 06/23/2024] [Indexed: 06/30/2024]
Abstract
OBJECTIVE The molecular control of feeding after fasting is essential for maintaining energy homeostasis, while overfeeding usually leads to obesity. Identifying non-coding microRNAs (miRNAs) that control food intake could reveal new oligonucleotide-based therapeutic targets for treating obesity and its associated diseases. This study aims to identify a miRNA modulating food intake and its mechanism in neuronal regulation of food intake and energy homeostasis. METHODS A comprehensive genome-wide miRNA screening in the arcuate nucleus of the hypothalamus (ARC) of fasted mice and ad libitum mice was performed. Through stereotactic virus injections, intracerebroventricular injections, and miRNA sponge technology, miR-7a-5p was inhibited specifically in AgRP neurons and the central nervous system, and metabolic phenotypes were monitored. Quantitative real-time PCR, Western blotting, immunofluorescence, whole-cell patch-clamp recording, and luciferase reporter assay were used to investigate the mechanisms underlying miR-7a-5p's regulation of food intake. RESULTS We found a significant increase in miR-7a-5p levels after fasting. miR-7a-5p was highly expressed in the ARC, and inhibition of miR-7a-5p specifically in AgRP neurons reduced food intake and body weight gain. miR-7a-5p inhibited S6K1 gene expression by binding to its 3'-UTR. Furthermore, the knockdown of ribosomal S6 kinase 1 (S6K1) in AgRP neurons can partially reverse the effects caused by miR-7a-5p inhibition. Importantly, intracerebroventricular administration of the miR-7a-5p inhibitor could also reduce food intake and body weight gain. CONCLUSION Our findings suggest that miR-7a-5p responds to energy deficit and regulates food intake by fine-tuning mTOR1/S6K1 signaling in the AgRP neurons, which could be a promising oligonucleotide-based therapeutic target for treating obesity and its associated diseases.
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Affiliation(s)
- Mingyang Yuan
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, SJTUSM, Shanghai, China
| | - Zhiwen Cao
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, SJTUSM, Shanghai, China
| | - Qian Li
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, SJTUSM, Shanghai, China
| | - Ruixin Liu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, SJTUSM, Shanghai, China
| | - Jiqiu Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, SJTUSM, Shanghai, China.
| | - Wenzhi Xue
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, SJTUSM, Shanghai, China; Clinical Neuroscience Center, Ruijin Hospital Luwan Branch, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
| | - Qianqian Lyu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, SJTUSM, Shanghai, China.
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Carbone F, Colamatteo A, La Rocca C, Lepore MT, Russo C, De Rosa G, Matarese A, Procaccini C, Matarese G. Metabolic Plasticity of Regulatory T Cells in Health and Autoimmunity. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1859-1866. [PMID: 38830147 DOI: 10.4049/jimmunol.2400079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 04/05/2024] [Indexed: 06/05/2024]
Abstract
Immunometabolism has been demonstrated to control immune tolerance and the pathogenic events leading to autoimmunity. Compelling experimental evidence also suggests that intracellular metabolic programs influence differentiation, phenotype, proliferation, and effector functions of anti-inflammatory CD4+CD25+Foxp3+ regulatory T (Treg) cells. Indeed, alterations in intracellular metabolism associate with quantitative and qualitative impairments of Treg cells in several pathological conditions. In this review, we summarize the most recent advances linking how metabolic pathways control Treg cell homeostasis and their alterations occurring in autoimmunity. Also, we analyze how metabolic manipulations could be employed to restore Treg cell frequency and function with the aim to create novel therapeutic opportunities to halt immune-mediated disorders.
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Grants
- 2022LNHZAP Ministero dell''''Istruzione, dell''''Università e della Ricerca (MIUR)
- PE00000007 Ministero dell''''Istruzione, dell''''Università e della Ricerca (MIUR)
- PE00000006 Ministero dell''''Istruzione, dell''''Università e della Ricerca (MIUR)
- RF-2019-12371111 Italy Ministry of Health | Agenzia Italiana del Farmaco, Ministero della Salute (AIFA)
- PNRR-MAD-2022-12375634 Italy Ministry of Health | Agenzia Italiana del Farmaco, Ministero della Salute (AIFA)
- GR-2018-12366154 Italy Ministry of Health | Agenzia Italiana del Farmaco, Ministero della Salute (AIFA)
- 2022-PRsingle/013 Fondazione Italiana Sclerosi Multipla (FISM)
- P2022T4PKT Ministero dell''''Istruzione, dell''''Università e della Ricerca (MIUR)
- PNRR-MAD-2022-12376126 Italy Ministry of Health | Agenzia Italiana del Farmaco, Ministero della Salute (AIFA)
- GR-2021-12373337 Italy Ministry of Health | Agenzia Italiana del Farmaco, Ministero della Salute (AIFA)
- 2022YMJXYT Ministero dell''''Istruzione, dell''''Università e della Ricerca (MIUR)
- P2022CMK43 Ministero dell''''Istruzione, dell''''Università e della Ricerca (MIUR)
- 20225KH7BZ Ministero dell''''Istruzione, dell''''Università e della Ricerca (MIUR)
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Affiliation(s)
- Fortunata Carbone
- Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale "G. Salvatore," Consiglio Nazionale delle Ricerche, Napoli, Italy
- Unità di Neuroimmunologia, IRCCS-Fondazione Santa Lucia, Roma, Italy
| | - Alessandra Colamatteo
- Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II," Napoli, Italy
| | - Claudia La Rocca
- Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale "G. Salvatore," Consiglio Nazionale delle Ricerche, Napoli, Italy
| | - Maria Teresa Lepore
- Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale "G. Salvatore," Consiglio Nazionale delle Ricerche, Napoli, Italy
| | - Claudia Russo
- D.A.I. Medicina di Laboratorio e Trasfusionale, Azienda Ospedaliera Universitaria "Federico II," Napoli, Italy
| | - Giusy De Rosa
- Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II," Napoli, Italy
| | - Alessandro Matarese
- Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli "Federico II," Napoli, Italy
| | - Claudio Procaccini
- Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale "G. Salvatore," Consiglio Nazionale delle Ricerche, Napoli, Italy
- Unità di Neuroimmunologia, IRCCS-Fondazione Santa Lucia, Roma, Italy
| | - Giuseppe Matarese
- Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale "G. Salvatore," Consiglio Nazionale delle Ricerche, Napoli, Italy
- Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II," Napoli, Italy
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Volyanskaya AR, Akberdin IR, Kulyashov MA, Yevshin IS, Romanov MN, Shagimardanova EI, Gusev OA, Kolpakov FA. A bird's-eye overview of molecular mechanisms regulating feed intake in chickens-with mammalian comparisons. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2024; 17:61-74. [PMID: 38737579 PMCID: PMC11087724 DOI: 10.1016/j.aninu.2024.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 12/29/2023] [Accepted: 01/10/2024] [Indexed: 05/14/2024]
Abstract
In recent decades, a lot of research has been conducted to explore poultry feeding behavior. However, up to now, the processes behind poultry feeding behavior remain poorly understood. The review generalizes modern expertise about the hormonal regulation of feeding behavior in chickens, focusing on signaling pathways mediated by insulin, leptin, and ghrelin and regulatory pathways with a cross-reference to mammals. This overview also summarizes state-of-the-art research devoted to hypothalamic neuropeptides that control feed intake and are prime candidates for predictors of feeding efficiency. Comparative analysis of the signaling pathways that mediate the feed intake regulation allowed us to conclude that there are major differences in the processes by which hormones influence specific neuropeptides and their contrasting roles in feed intake control between two vertebrate clades.
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Affiliation(s)
- Anastasiia R. Volyanskaya
- Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russia
- Biosoft.Ru, Ltd., Novosibirsk, Russia
| | - Ilya R. Akberdin
- Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russia
- Biosoft.Ru, Ltd., Novosibirsk, Russia
- Sirius University of Science and Technology, Sirius, Russia
| | - Mikhail A. Kulyashov
- Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russia
- Biosoft.Ru, Ltd., Novosibirsk, Russia
- Sirius University of Science and Technology, Sirius, Russia
| | - Ivan S. Yevshin
- Biosoft.Ru, Ltd., Novosibirsk, Russia
- Sirius University of Science and Technology, Sirius, Russia
| | - Michael N. Romanov
- School of Biosciences, University of Kent, Canterbury, UK
- L.K. Ernst Federal Research Centre for Animal Husbandry, Dubrovitsy, Podolsk, Russia
| | - Elena I. Shagimardanova
- Regulatory Genomics Research Center, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Oleg A. Gusev
- Regulatory Genomics Research Center, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
- Life Improvement By Future Technologies (LIFT) Center, Moscow, Russia
- Intractable Disease Research Center, Juntendo University, Tokyo, Japan
| | - Fedor A. Kolpakov
- Biosoft.Ru, Ltd., Novosibirsk, Russia
- Sirius University of Science and Technology, Sirius, Russia
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Allard C, Miralpeix C, López-Gambero AJ, Cota D. mTORC1 in energy expenditure: consequences for obesity. Nat Rev Endocrinol 2024; 20:239-251. [PMID: 38225400 DOI: 10.1038/s41574-023-00934-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/29/2023] [Indexed: 01/17/2024]
Abstract
In eukaryotic cells, the mammalian target of rapamycin complex 1 (sometimes referred to as the mechanistic target of rapamycin complex 1; mTORC1) orchestrates cellular metabolism in response to environmental energy availability. As a result, at the organismal level, mTORC1 signalling regulates the intake, storage and use of energy by acting as a hub for the actions of nutrients and hormones, such as leptin and insulin, in different cell types. It is therefore unsurprising that deregulated mTORC1 signalling is associated with obesity. Strategies that increase energy expenditure offer therapeutic promise for the treatment of obesity. Here we review current evidence illustrating the critical role of mTORC1 signalling in the regulation of energy expenditure and adaptive thermogenesis through its various effects in neuronal circuits, adipose tissue and skeletal muscle. Understanding how mTORC1 signalling in one organ and cell type affects responses in other organs and cell types could be key to developing better, safer treatments targeting this pathway in obesity.
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Affiliation(s)
- Camille Allard
- University of Bordeaux, INSERM, Neurocentre Magendie, Bordeaux, France
| | | | | | - Daniela Cota
- University of Bordeaux, INSERM, Neurocentre Magendie, Bordeaux, France.
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Engin A. Protein Kinases in Obesity, and the Kinase-Targeted Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:199-229. [PMID: 39287853 DOI: 10.1007/978-3-031-63657-8_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
The action of protein kinases and protein phosphatases is essential for multiple physiological responses. Each protein kinase displays its own unique substrate specificity and a regulatory mechanism that may be modulated by association with other proteins. Protein kinases are classified as dual-specificity kinases and dual-specificity phosphatases. Dual-specificity phosphatases are important signal transduction enzymes that regulate various cellular processes in coordination with protein kinases and play an important role in obesity. Impairment of insulin signaling in obesity is largely mediated by the activation of the inhibitor of kappa B-kinase beta and the c-Jun N-terminal kinase (JNK). Oxidative stress and endoplasmic reticulum (ER) stress activate the JNK pathway which suppresses insulin biosynthesis. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are important for proper regulation of glucose metabolism in mammals at both the hormonal and cellular levels. Additionally, obesity-activated calcium/calmodulin dependent-protein kinase II/p38 suppresses insulin-induced protein kinase B phosphorylation by activating the ER stress effector, activating transcription factor-4. To alleviate lipotoxicity and insulin resistance, promising targets are pharmacologically inhibited. Nifedipine, calcium channel blocker, stimulates lipogenesis and adipogenesis by downregulating AMPK and upregulating mTOR, which thereby enhances lipid storage. Contrary to the nifedipine, metformin activates AMPK, increases fatty acid oxidation, suppresses fatty acid synthesis and deposition, and thus alleviates lipotoxicity. Obese adults with vascular endothelial dysfunction have greater endothelial cells activation of unfolded protein response stress sensors, RNA-dependent protein kinase-like ER eukaryotic initiation factor-2 alpha kinase (PERK), and activating transcription factor-6. The transcriptional regulation of adipogenesis in obesity is influenced by AGC (protein kinase A (PKA), PKG, PKC) family signaling kinases. Obesity may induce systemic oxidative stress and increase reactive oxygen species in adipocytes. An increase in intracellular oxidative stress can promote PKC-β activation. Activated PKC-β induces growth factor adapter Shc phosphorylation. Shc-generated peroxides reduce mitochondrial oxygen consumption and enhance triglyceride accumulation and lipotoxicity. Liraglutide attenuates mitochondrial dysfunction and reactive oxygen species generation. Co-treatment of antiobesity and antidiabetic herbal compound, berberine with antipsychotic drug olanzapine decreases the accumulation of triglyceride. While low-dose rapamycin, metformin, amlexanox, thiazolidinediones, and saroglitazar protect against insulin resistance, glucagon-like peptide-1 analog liraglutide inhibits palmitate-induced inflammation by suppressing mTOR complex 1 (mTORC1) activity and protects against lipotoxicity.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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Xin S, Xiaoxuan L, Yixuan Z, Zhikang C. Leptin promotes proliferation of human undifferentiated spermatogonia by activating the PI3K/AKT/mTOR pathway. Am J Reprod Immunol 2024; 91:e13811. [PMID: 38282611 DOI: 10.1111/aji.13811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 12/17/2023] [Accepted: 12/29/2023] [Indexed: 01/30/2024] Open
Abstract
BACKGROUND Male infertility is a common disease affecting male reproductive health. Leptin is an important hormone that regulates various physiological processes, including reproductive function. However, few experimental studies have been carried out to elucidate the mechanism of leptin's effects on male reproductive function. OBJECTIVE The purpose of this study was to investigate the effects of leptin on testicular spermatogenesis and its mechanism, so as to provide potential targets for the treatment of patients with spermatogenic dysfunction. METHODS Testicular tissues were collected from eight prostate cancer patients undergoing surgical castration. GPR125-positive spermatogonia were isolated by two consecutive magnetic activated cell sorting (MACS), followed by incubation with conditioned medium. To identify the signaling pathway(s) involved in the effects of leptin, undifferentiated spermatogonia were treated with different concentrations of leptin and antagonists of leptin-related pathways. The proliferative effect of leptin was evaluated by cell counting using a hemocytometer. Expressions of p-AKT, p-ERK, p-STAT, and p-S6K were determined by western blotting analysis. RESULTS Leptin promoted the growth of human GPR125-positive spermatogonia in a concentration-dependent manner. The most significant proliferative effect was observed using 100 ng/mL leptin after 6 days of culture. Leptin significantly increased the phosphorylation of STAT3, AKT, and ERK in undifferentiated spermatogonia. Phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 inhibited the leptin-induced activation of AKT, ERK, and downstream S6K. Treatment with the mammalian target of rapamycin (mTOR) inhibitor rapamycin also inhibited S6K phosphorylation. Moreover, both LY294002 and rapamycin were found to inhibit the leptin-induced proliferation of undifferentiated spermatogonia. These results suggested that the leptin-induced proliferation of GPR125-positive spermatogonia was dependent on the PI3K/AKT/mTOR pathway. Further exploration of proliferation and apoptotic markers suggested that leptin may alleviate cell apoptosis by regulating the expression of Bax and FasL. CONCLUSIONS A certain concentration of leptin (25∼100 ng/mL) could promote proliferation of undifferentiated spermatogonia, which was mediated by PI3K/AKT/mTOR pathway.
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Affiliation(s)
- Song Xin
- Department of Urology, Gongli Hospital of Shanghai Pudong New Area, Shanghai, China
| | - Li Xiaoxuan
- School of Medicine, Qingdao University, Qingdao, China
| | - Zhang Yixuan
- School of Medicine, Qingdao University, Qingdao, China
| | - Cai Zhikang
- Department of Urology, Gongli Hospital of Shanghai Pudong New Area, Shanghai, China
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Engin A. The Mechanism of Leptin Resistance in Obesity and Therapeutic Perspective. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:463-487. [PMID: 39287862 DOI: 10.1007/978-3-031-63657-8_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Leptin resistance is induced via leptin signaling blockade by chronic overstimulation of the leptin receptor and intracellular signaling defect or increased hypothalamic inflammation and suppressor of cytokine signaling (SOCS)-3 expression. High-fat diet triggers leptin resistance induced by at least two independent causes: first, the limited ability of peripheral leptin to activate hypothalamic signaling transducers and activators of transcription (STAT) signaling and secondly a signaling defect in leptin-responsive hypothalamic neurons. Central leptin resistance is dependent on decreased leptin transport efficiency across the blood brain barrier (BBB) rather than hypothalamic leptin insensitivity. Since the hypothalamic phosphorylated STAT3 (pSTAT3) represents a sensitive and specific readout of leptin receptor-B signaling, the assessment of pSTAT3 levels is the gold standard. Hypertriglyceridemia is one of important factors to inhibit the transport of leptin across BBB in obesity. Mismatch between high leptin and the amount of leptin receptor expression in obesity triggers brain leptin resistance via increasing hypothalamic inflammation and SOCS-3 expression. Therapeutic strategies that regulate the passage of leptin to the brain include the development of modifications in the structure of leptin analogues as well as the synthesis of new leptin receptor agonists with increased BBB permeability. In the hyperleptinemic state, polyethylene glycol (PEG)-modified leptin is unable to pass through the BBB. Peripheral histone deacetylase (HDAC) 6 inhibitor, tubastatin, and metformin increase central leptin sensitization. While add-on therapy with anagliptin, metformin and miglitol reduce leptin concentrations, the use of long-acting leptin analogs, and exendin-4 lead to the recovery of leptin sensitivity. Contouring surgery with fat removal, and bariatric surgery independently of the type of surgery performed provide significant improvement in leptin concentrations. Although approaches to correcting leptin resistance have shown some success, no clinically effective application has been developed to date. Due to the impairment of central and peripheral leptin signaling, as well as the extensive integration of leptin-sensitive metabolic pathways with other neurons, the effectiveness of methods used to eliminate leptin resistance is extremely limited.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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Le TDV, Liu D, Besing GLK, Raghavan R, Ellis BJ, Ceddia RP, Collins S, Ayala JE. Glucagon-like peptide-1 receptor activation stimulates PKA-mediated phosphorylation of Raptor and this contributes to the weight loss effect of liraglutide. eLife 2023; 12:e80944. [PMID: 37930356 PMCID: PMC10691799 DOI: 10.7554/elife.80944] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 11/03/2023] [Indexed: 11/07/2023] Open
Abstract
The canonical target of the glucagon-like peptide-1 receptor (GLP-1R), Protein Kinase A (PKA), has been shown to stimulate mechanistic Target of Rapamycin Complex 1 (mTORC1) by phosphorylating the mTOR-regulating protein Raptor at Ser791 following β-adrenergic stimulation. The objective of these studies is to test whether GLP-1R agonists similarly stimulate mTORC1 via PKA phosphorylation of Raptor at Ser791 and whether this contributes to the weight loss effect of the therapeutic GLP-1R agonist liraglutide. We measured phosphorylation of the mTORC1 signaling target ribosomal protein S6 in Chinese Hamster Ovary cells expressing GLP-1R (CHO-Glp1r) treated with liraglutide in combination with PKA inhibitors. We also assessed liraglutide-mediated phosphorylation of the PKA substrate RRXS*/T* motif in CHO-Glp1r cells expressing Myc-tagged wild-type (WT) Raptor or a PKA-resistant (Ser791Ala) Raptor mutant. Finally, we measured the body weight response to liraglutide in WT mice and mice with a targeted knock-in of PKA-resistant Ser791Ala Raptor. Liraglutide increased phosphorylation of S6 and the PKA motif in WT Raptor in a PKA-dependent manner but failed to stimulate phosphorylation of the PKA motif in Ser791Ala Raptor in CHO-Glp1r cells. Lean Ser791Ala Raptor knock-in mice were resistant to liraglutide-induced weight loss but not setmelanotide-induced (melanocortin-4 receptor-dependent) weight loss. Diet-induced obese Ser791Ala Raptor knock-in mice were not resistant to liraglutide-induced weight loss; however, there was weight-dependent variation such that there was a tendency for obese Ser791Ala Raptor knock-in mice of lower relative body weight to be resistant to liraglutide-induced weight loss compared to weight-matched controls. Together, these findings suggest that PKA-mediated phosphorylation of Raptor at Ser791 contributes to liraglutide-induced weight loss.
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Affiliation(s)
- Thao DV Le
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of MedicineNashvilleUnited States
| | - Dianxin Liu
- Department of Medicine, Vanderbilt University Medical CenterNashvilleUnited States
| | - Gai-Linn K Besing
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of MedicineNashvilleUnited States
| | - Ritika Raghavan
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of MedicineNashvilleUnited States
| | - Blair J Ellis
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of MedicineNashvilleUnited States
| | - Ryan P Ceddia
- Department of Medicine, Vanderbilt University Medical CenterNashvilleUnited States
| | - Sheila Collins
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of MedicineNashvilleUnited States
- Department of Medicine, Vanderbilt University Medical CenterNashvilleUnited States
| | - Julio E Ayala
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of MedicineNashvilleUnited States
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10
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Liu Z, Xiao T, Liu H. Leptin signaling and its central role in energy homeostasis. Front Neurosci 2023; 17:1238528. [PMID: 38027481 PMCID: PMC10644276 DOI: 10.3389/fnins.2023.1238528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 10/17/2023] [Indexed: 12/01/2023] Open
Abstract
Leptin plays a critical role in regulating appetite, energy expenditure and body weight, making it a key factor in maintaining a healthy balance. Despite numerous efforts to develop therapeutic interventions targeting leptin signaling, their effectiveness has been limited, underscoring the importance of gaining a better understanding of the mechanisms through which leptin exerts its functions. While the hypothalamus is widely recognized as the primary site responsible for the appetite-suppressing and weight-reducing effects of leptin, other brain regions have also been increasingly investigated for their involvement in mediating leptin's action. In this review, we summarize leptin signaling pathways and the neural networks that mediate the effects of leptin, with a specific emphasis on energy homeostasis.
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Affiliation(s)
- Zhaoxun Liu
- Nursing Department, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Emergency, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Tao Xiao
- Nursing Department, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hailan Liu
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
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11
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de Souza GO, Teixeira PDS, Câmara NOS, Donato J. mTORC1 Signaling in AgRP Neurons Is Not Required to Induce Major Neuroendocrine Adaptations to Food Restriction. Cells 2023; 12:2442. [PMID: 37887286 PMCID: PMC10605346 DOI: 10.3390/cells12202442] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/04/2023] [Accepted: 10/09/2023] [Indexed: 10/28/2023] Open
Abstract
Hypothalamic mTORC1 signaling is involved in nutrient sensing. Neurons that express the agouti-related protein (AgRP) are activated by food restriction and integrate interoceptive and exteroceptive signals to control food intake, energy expenditure, and other metabolic responses. To determine whether mTORC1 signaling in AgRP neurons is necessary for regulating energy and glucose homeostasis, especially in situations of negative energy balance, mice carrying ablation of the Raptor gene exclusively in AgRP-expressing cells were generated. AgRPΔRaptor mice showed no differences in body weight, fat mass, food intake, or energy expenditure; however, a slight improvement in glucose homeostasis was observed compared to the control group. When subjected to 5 days of food restriction (40% basal intake), AgRPΔRaptor female mice lost less lean body mass and showed a blunted reduction in energy expenditure, whereas AgRPΔRaptor male mice maintained a higher energy expenditure compared to control mice during the food restriction and 5 days of refeeding period. AgRPΔRaptor female mice did not exhibit the food restriction-induced increase in serum corticosterone levels. Finally, although hypothalamic fasting- or refeeding-induced Fos expression showed no differences between the groups, AgRPΔRaptor mice displayed increased hyperphagia during refeeding. Thus, some metabolic and neuroendocrine responses to food restriction are disturbed in AgRPΔRaptor mice.
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Affiliation(s)
- Gabriel O. de Souza
- Departamento de Fisiologia e Biofisica, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo 05508-000, SP, Brazil; (G.O.d.S.); (P.D.S.T.)
| | - Pryscila D. S. Teixeira
- Departamento de Fisiologia e Biofisica, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo 05508-000, SP, Brazil; (G.O.d.S.); (P.D.S.T.)
| | - Niels O. S. Câmara
- Departamento de Imunologia, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo 05508-000, SP, Brazil;
| | - Jose Donato
- Departamento de Fisiologia e Biofisica, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo 05508-000, SP, Brazil; (G.O.d.S.); (P.D.S.T.)
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12
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Metaxakis A, Pavlidis M, Tavernarakis N. Neuronal atg1 Coordinates Autophagy Induction and Physiological Adaptations to Balance mTORC1 Signalling. Cells 2023; 12:2024. [PMID: 37626835 PMCID: PMC10453232 DOI: 10.3390/cells12162024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/04/2023] [Accepted: 08/05/2023] [Indexed: 08/27/2023] Open
Abstract
The mTORC1 nutrient-sensing pathway integrates metabolic and endocrine signals into the brain to evoke physiological responses to food deprivation, such as autophagy. Nevertheless, the impact of neuronal mTORC1 activity on neuronal circuits and organismal metabolism remains obscure. Here, we show that mTORC1 inhibition acutely perturbs serotonergic neurotransmission via proteostatic alterations evoked by the autophagy inducer atg1. Neuronal ATG1 alters the intracellular localization of the serotonin transporter, which increases the extracellular serotonin and stimulates the 5HTR7 postsynaptic receptor. 5HTR7 enhances food-searching behaviour and ecdysone-induced catabolism in Drosophila. Along similar lines, the pharmacological inhibition of mTORC1 in zebrafish also stimulates food-searching behaviour via serotonergic activity. These effects occur in parallel with neuronal autophagy induction, irrespective of the autophagic activity and the protein synthesis reduction. In addition, ectopic neuronal atg1 expression enhances catabolism via insulin pathway downregulation, impedes peptidergic secretion, and activates non-cell autonomous cAMP/PKA. The above exert diverse systemic effects on organismal metabolism, development, melanisation, and longevity. We conclude that neuronal atg1 aligns neuronal autophagy induction with distinct physiological modulations, to orchestrate a coordinated physiological response against reduced mTORC1 activity.
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Affiliation(s)
- Athanasios Metaxakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas, Nikolaou Plastira 100, 70013 Heraklion, Crete, Greece
| | - Michail Pavlidis
- Department of Biology, University of Crete, 71409 Heraklion, Crete, Greece;
| | - Nektarios Tavernarakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas, Nikolaou Plastira 100, 70013 Heraklion, Crete, Greece
- Department of Basic Sciences, Faculty of Medicine, University of Crete, 71110 Heraklion, Crete, Greece
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13
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Zakharova IO, Bayunova LV, Derkach KV, Ilyasov IO, Morina IY, Shpakov AO, Avrova NF. Effects of Intranasally Administered Insulin and Gangliosides on Hypothalamic Signaling and Expression of Hepatic Gluconeogenesis Genes in Rats with Type 2 Diabetes Mellitus. J EVOL BIOCHEM PHYS+ 2022. [DOI: 10.1134/s0022093022060072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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14
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Comesaña S, Chivite M, Blanco AM, Alborja-Valado M, Calo J, Conde-Sieira M, Soengas JL. Involvement of Mechanistic Target of Rapamycin (mTOR) in Valine Orexigenic Effects in Rainbow Trout. AQUACULTURE NUTRITION 2022; 2022:7509382. [PMID: 36860456 PMCID: PMC9973124 DOI: 10.1155/2022/7509382] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/06/2022] [Accepted: 09/14/2022] [Indexed: 06/18/2023]
Abstract
This study was aimed at clarifying the importance of a mechanistic target of rapamycin (mTOR) in the central orexigenic effect of valine in fish. For this, rainbow trout (Oncorhynchus mykiss) were intracerebroventricularly (ICV) injected with valine alone or in the presence of rapamycin as the mTOR inhibitor, and two experiments were performed. In the first experiment, we evaluated feed intake levels. In the second experiment, we evaluated in the hypothalamus and telencephalon the following: (1) the phosphorylation status of mTOR and its downstream effectors ribosomal protein S6 and p70 S6 kinase 1 (S6K1), (2) the abundance and phosphorylation status of transcription factors involved in appetite regulation, and (3) the mRNA levels of key neuropeptides associated with homeostatic regulation of feed intake in fish. Rising central levels of valine clearly resulted in an orexigenic response in rainbow trout. This response occurred in parallel with mTOR activation in both the hypothalamus and telencephalon, as supported by depressant changes in proteins involved in mTOR signalling (S6 and S6K1). Also, these changes disappeared in the presence of rapamycin. However, it is not clear which precise mechanisms link the activation of mTOR and the alteration in feed intake levels since we did not observe changes in mRNA levels of appetite-regulatory neuropeptides as well as in the phosphorylation status and levels of integrative proteins.
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Affiliation(s)
- Sara Comesaña
- Centro de Investigación Mariña, Laboratorio de Fisioloxía Animal, Departamento de Bioloxía Funcional e Ciencias da Saúde, Facultade de Bioloxía, Universidade de Vigo, E-36310 Vigo, Spain
| | - Mauro Chivite
- Centro de Investigación Mariña, Laboratorio de Fisioloxía Animal, Departamento de Bioloxía Funcional e Ciencias da Saúde, Facultade de Bioloxía, Universidade de Vigo, E-36310 Vigo, Spain
| | - Ayelén M. Blanco
- Centro de Investigación Mariña, Laboratorio de Fisioloxía Animal, Departamento de Bioloxía Funcional e Ciencias da Saúde, Facultade de Bioloxía, Universidade de Vigo, E-36310 Vigo, Spain
| | - María Alborja-Valado
- Centro de Investigación Mariña, Laboratorio de Fisioloxía Animal, Departamento de Bioloxía Funcional e Ciencias da Saúde, Facultade de Bioloxía, Universidade de Vigo, E-36310 Vigo, Spain
| | - Jessica Calo
- Centro de Investigación Mariña, Laboratorio de Fisioloxía Animal, Departamento de Bioloxía Funcional e Ciencias da Saúde, Facultade de Bioloxía, Universidade de Vigo, E-36310 Vigo, Spain
| | - Marta Conde-Sieira
- Centro de Investigación Mariña, Laboratorio de Fisioloxía Animal, Departamento de Bioloxía Funcional e Ciencias da Saúde, Facultade de Bioloxía, Universidade de Vigo, E-36310 Vigo, Spain
| | - José L. Soengas
- Centro de Investigación Mariña, Laboratorio de Fisioloxía Animal, Departamento de Bioloxía Funcional e Ciencias da Saúde, Facultade de Bioloxía, Universidade de Vigo, E-36310 Vigo, Spain
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15
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Kappa-Opioid Receptor Blockade Ameliorates Obesity Caused by Estrogen Withdrawal via Promotion of Energy Expenditure through mTOR Pathway. Int J Mol Sci 2022; 23:ijms23063118. [PMID: 35328539 PMCID: PMC8953356 DOI: 10.3390/ijms23063118] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/25/2022] [Accepted: 03/11/2022] [Indexed: 12/11/2022] Open
Abstract
Weight gain is a hallmark of decreased estradiol (E2) levels because of menopause or following surgical ovariectomy (OVX) at younger ages. Of note, this weight gain tends to be around the abdomen, which is frequently associated with impaired metabolic homeostasis and greater cardiovascular risk in both rodents and humans. However, the molecular underpinnings and the neuronal basis for these effects remain to be elucidated. The aim of this study is to elucidate whether the kappa-opioid receptor (k-OR) system is involved in mediating body weight changes associated with E2 withdrawal. Here, we document that body weight gain induced by OVX occurs, at least partially, in a k-OR dependent manner, by modulation of energy expenditure independently of food intake as assessed in Oprk1−/−global KO mice. These effects were also observed following central pharmacological blockade of the k-OR system using the k-OR-selective antagonist PF-04455242 in wild type mice, in which we also observed a decrease in OVX-induced weight gain associated with increased UCP1 positive immunostaining in brown adipose tissue (BAT) and browning of white adipose tissue (WAT). Remarkably, the hypothalamic mTOR pathway plays an important role in regulating weight gain and adiposity in OVX mice. These findings will help to define new therapies to manage metabolic disorders associated with low/null E2 levels based on the modulation of central k-OR signaling.
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16
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Häusl AS, Bajaj T, Brix LM, Pöhlmann ML, Hafner K, De Angelis M, Nagler J, Dethloff F, Balsevich G, Schramm KW, Giavalisco P, Chen A, Schmidt MV, Gassen NC. Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to whole-body metabolism. SCIENCE ADVANCES 2022; 8:eabi4797. [PMID: 35263141 PMCID: PMC8906734 DOI: 10.1126/sciadv.abi4797] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/15/2023]
Abstract
The mediobasal hypothalamus (MBH) is the central region in the physiological response to metabolic stress. The FK506-binding protein 51 (FKBP51) is a major modulator of the stress response and has recently emerged as a scaffolder regulating metabolic and autophagy pathways. However, the detailed protein-protein interactions linking FKBP51 to autophagy upon metabolic challenges remain elusive. We performed mass spectrometry-based metabolomics of FKBP51 knockout (KO) cells revealing an increased amino acid and polyamine metabolism. We identified FKBP51 as a central nexus for the recruitment of the LKB1/AMPK complex to WIPI4 and TSC2 to WIPI3, thereby regulating the balance between autophagy and mTOR signaling in response to metabolic challenges. Furthermore, we demonstrated that MBH FKBP51 deletion strongly induces obesity, while its overexpression protects against high-fat diet (HFD)-induced obesity. Our study provides an important novel regulatory function of MBH FKBP51 within the stress-adapted autophagy response to metabolic challenges.
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Affiliation(s)
- Alexander S. Häusl
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804 Munich, Germany
| | - Thomas Bajaj
- Neurohomeostasis Research Group, Department of Psychiatry and Psychotherapy, Bonn Clinical Center, University of Bonn, 53127 Bonn, Germany
| | - Lea M. Brix
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804 Munich, Germany
- International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Kraepelinstr. 2-10, 80804 Munich, Germany
| | - Max L. Pöhlmann
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804 Munich, Germany
| | - Kathrin Hafner
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany
| | - Meri De Angelis
- Helmholtz Center Munich Germany Research Center for Environmental Health, Molecular EXposomics, Neuherberg, Germany
| | - Joachim Nagler
- Helmholtz Center Munich Germany Research Center for Environmental Health, Molecular EXposomics, Neuherberg, Germany
| | | | - Georgia Balsevich
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804 Munich, Germany
| | - Karl-Werner Schramm
- Helmholtz Center Munich Germany Research Center for Environmental Health, Molecular EXposomics, Neuherberg, Germany
| | | | - Alon Chen
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, 80804 Munich, Germany
- Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel
| | - Mathias V. Schmidt
- Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80804 Munich, Germany
- Corresponding author. (M.V.S.); (N.C.G.)
| | - Nils C. Gassen
- Neurohomeostasis Research Group, Department of Psychiatry and Psychotherapy, Bonn Clinical Center, University of Bonn, 53127 Bonn, Germany
- Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany
- Corresponding author. (M.V.S.); (N.C.G.)
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17
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Yi SA, Jeon YJ, Lee MG, Nam KH, Ann S, Lee J, Han JW. S6K1 controls adiponectin expression by inducing a transcriptional switch: BMAL1-to-EZH2. Exp Mol Med 2022; 54:324-333. [PMID: 35338256 PMCID: PMC8979988 DOI: 10.1038/s12276-022-00747-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 12/03/2021] [Accepted: 12/29/2021] [Indexed: 11/24/2022] Open
Abstract
Adiponectin (encoded by Adipoq), a fat-derived hormone, alleviates risk factors associated with metabolic disorders. Although many transcription factors are known to control adiponectin expression, the mechanism underlying its fluctuation with regard to metabolic status remains unclear. Here, we show that ribosomal protein S6 kinase 1 (S6K1) controls adiponectin expression by inducing a transcriptional switch between two transcriptional machineries, BMAL1 and EZH2. Active S6K1 induced a suppressive histone code cascade, H2BS36p-EZH2-H3K27me3, leading to suppression of adiponectin expression. Moreover, active S6K1 phosphorylated BMAL1, an important transcription factor regulating the circadian clock system, at serine 42, which led to its dissociation from the Adipoq promoter region. This response resulted in EZH2 recruitment and subsequent H3K27me3 modification of the Adipoq promoter. Upon fasting, inactivation of S6K1 induced the opposite transcriptional switch, EZH2-to-BMAL1, promoting adiponectin expression. Consistently, S6K1-depleted mice exhibited lower H3K27me3 levels and elevated adiponectin expression. These findings identify a novel epigenetic switch system by which S6K1 controls the production of adiponectin, which displays beneficial effects on metabolism.
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Affiliation(s)
- Sang Ah Yi
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
| | - Ye Ji Jeon
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Min Gyu Lee
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Ki Hong Nam
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Sora Ann
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Jaecheol Lee
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
- Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon, 16419, Korea.
- Imnewrun Biosciences, Inc, Suwon, 16419, Korea.
| | - Jeung-Whan Han
- School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
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18
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Abstract
BACKGROUND Obesity develops due to an imbalance in energy homeostasis, wherein energy intake exceeds energy expenditure. Accumulating evidence shows that manipulations of dietary protein and their component amino acids affect the energy balance, resulting in changes in fat mass and body weight. Amino acids are not only the building blocks of proteins but also serve as signals regulating multiple biological pathways. SCOPE OF REVIEW We present the currently available evidence regarding the effects of dietary alterations of a single essential amino acid (EAA) on energy balance and relevant signaling mechanisms at both central and peripheral levels. We summarize the association between EAAs and obesity in humans and the clinical use of modifying the dietary EAA composition for therapeutic intervention in obesity. Finally, similar mechanisms underlying diets varying in protein levels and diets altered of a single EAA are described. The current review would expand our understanding of the contribution of protein and amino acids to energy balance control, thus helping discover novel therapeutic approaches for obesity and related diseases. MAJOR CONCLUSIONS Changes in circulating EAA levels, particularly increased branched-chain amino acids (BCAAs), have been reported in obese human and animal models. Alterations in dietary EAA intake result in improvements in fat and weight loss in rodents, and each has its distinct mechanism. For example, leucine deprivation increases energy expenditure, reduces food intake and fat mass, primarily through regulation of the general control nonderepressible 2 (GCN2) and mammalian target of rapamycin (mTOR) signaling. Methionine restriction by 80% decreases fat mass and body weight while developing hyperphagia, primarily through fibroblast growth factor 21 (FGF-21) signaling. Some effects of diets with different protein levels on energy homeostasis are mediated by similar mechanisms. However, reports on the effects and underlying mechanisms of dietary EAA imbalances on human body weight are few, and more investigations are needed in future.
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Affiliation(s)
- Fei Xiao
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Innovation Center for Intervention of Chronic Disease and Promotion of Health, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China
| | - Feifan Guo
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Innovation Center for Intervention of Chronic Disease and Promotion of Health, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China; Shanghai Jiao Tong University Affiliated Sixth People's Hospital, China.
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19
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Vohra MS, Benchoula K, Serpell CJ, Hwa WE. AgRP/NPY and POMC neurons in the arcuate nucleus and their potential role in treatment of obesity. Eur J Pharmacol 2022; 915:174611. [PMID: 34798121 DOI: 10.1016/j.ejphar.2021.174611] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 10/27/2021] [Accepted: 10/27/2021] [Indexed: 02/08/2023]
Abstract
Obesity is a major health crisis affecting over a third of the global population. This multifactorial disease is regulated via interoceptive neural circuits in the brain, whose alteration results in excessive body weight. Certain central neuronal populations in the brain are recognised as crucial nodes in energy homeostasis; in particular, the hypothalamic arcuate nucleus (ARC) region contains two peptide microcircuits that control energy balance with antagonistic functions: agouti-related peptide/neuropeptide-Y (AgRP/NPY) signals hunger and stimulates food intake; and pro-opiomelanocortin (POMC) signals satiety and reduces food intake. These neuronal peptides levels react to energy status and integrate signals from peripheral ghrelin, leptin, and insulin to regulate feeding and energy expenditure. To manage obesity comprehensively, it is crucial to understand cellular and molecular mechanisms of information processing in ARC neurons, since these regulate energy homeostasis. Importantly, a specific strategy focusing on ARC circuits needs to be devised to assist in treating obese patients and maintaining weight loss with minimal or no side effects. The aim of this review is to elucidate the recent developments in the study of AgRP-, NPY- and POMC-producing neurons, specific to their role in controlling metabolism. The impact of ghrelin, leptin, and insulin signalling via action of these neurons is also surveyed, since they also impact energy balance through this route. Lastly, we present key proteins, targeted genes, compounds, drugs, and therapies that actively work via these neurons and could potentially be used as therapeutic targets for treating obesity conditions.
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Affiliation(s)
- Muhammad Sufyan Vohra
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University Lakeside Campus, 47500, Subang Jaya, Selangor Darul Ehsan, Malaysia
| | - Khaled Benchoula
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University Lakeside Campus, 47500, Subang Jaya, Selangor Darul Ehsan, Malaysia
| | - Christopher J Serpell
- School of Physical Sciences, Ingram Building, University of Kent, Canterbury, Kent, CT2 7NH, United Kingdom
| | - Wong Eng Hwa
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University Lakeside Campus, 47500, Subang Jaya, Selangor Darul Ehsan, Malaysia.
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20
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Bozadjieva Kramer N, Evers SS, Shin JH, Silverwood S, Wang Y, Burant CF, Sandoval DA, Seeley RJ. The Role of Elevated Branched-Chain Amino Acids in the Effects of Vertical Sleeve Gastrectomy to Reduce Weight and Improve Glucose Regulation. Cell Rep 2021; 33:108239. [PMID: 33053352 PMCID: PMC7605275 DOI: 10.1016/j.celrep.2020.108239] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 06/24/2020] [Accepted: 09/15/2020] [Indexed: 12/16/2022] Open
Abstract
Elevated levels of branched-chain amino acids (BCAAs) and their metabolites are strongly positively associated with obesity, insulin resistance, and type 2 diabetes. Bariatric surgery is among the best treatments for weight loss and associated morbidities. Clinical studies have reported that bariatric surgery decreases the circulating levels of BCAAs. The objective of this study was to test the hypothesis that reduced BCAA levels contribute to the metabolic improvements of sustained weight loss and improved glucose tolerance after vertical sleeve gastrectomy (VSG). We find that, as in humans, circulating BCAAs are significantly lower in VSG rats and mice. To increase circulating BCAAs, we tested mice with either increased dietary intake of BCAAs or impaired BCAA catabolism by total body deletion of mitochondrial phosphatase 2C (Pp2cm). Our results show that a decrease in circulating BCAAs is not necessary for sustained body weight loss and improved glucose tolerance after VSG. Increased branched-chain amino acid (BCAA) levels are biomarkers of metabolic disease, and bariatric surgeries reduce BCAA levels. Bozadjieva Kramer et al. show that both dietary and genetic manipulations can block the surgical effect on BCAAs but do not alter potent, beneficial effects on weight loss and glucose tolerance.
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Affiliation(s)
| | - Simon S Evers
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jae Hoon Shin
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Sierra Silverwood
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yibin Wang
- Departments of Anesthesiology, Medicine, and Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Charles F Burant
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | | | - Randy J Seeley
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
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21
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Einstein-Nathan Shock Center: translating the hallmarks of aging to extend human health span. GeroScience 2021; 43:2167-2182. [PMID: 34463901 DOI: 10.1007/s11357-021-00428-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 10/20/2022] Open
Abstract
The overarching mission of the Einstein-Nathan Shock Center (E-NSC) is to make scientific discoveries in geroscience, leveraging on the expertise in our center in 6 out of the 7 pillars of aging, and to translate their effects towards drug discovery. The relevance of this basic biology of aging discoveries to humans will be confirmed through the unique gero-human resource at E-NSC. This is achieved through services provided by E-NSC, connectivity among its members, attracting worldwide investigators, and providing them with the opportunities to become future leaders. The two central components of the E-NSC are (a) cutting-edge research programs and (b) unique E-NSC research support cores. E-NSC scientists lead NIH-supported cutting-edge research programs that integrate key hallmarks of aging including proteostasis/autophagy, metabolism/inflammaging, genetic/epigenetics, stem cells/regeneration, and translational aging/longevity. Since the inception of the E-NSC, the well-integrated, collaborative, and innovative nature of the multiple supporting state-of-the-art E-NSC research cores form the bedrock of research success at the E-NSC. The three state-of-the-art E-NSC research cores, (i) Proteostasis of Aging Core (PAC), (ii) the Health Span Core (HSC), and (iii) the Human Multi-Omics Core (HMOC), have allowed impressive expansion of translational biological research programs. Expansion was facilitated through the wealth of data coming from genomics/proteomics and metabolomic analysis on human longevity studies, due to access to a variety of biological samples from elderly subjects in clinical trials with aging-targeting drugs, and new drug design services via the PAC to target the hallmarks of aging.
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22
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23
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Abstract
Cells metabolize nutrients for biosynthetic and bioenergetic needs to fuel growth and proliferation. The uptake of nutrients from the environment and their intracellular metabolism is a highly controlled process that involves cross talk between growth signaling and metabolic pathways. Despite constant fluctuations in nutrient availability and environmental signals, normal cells restore metabolic homeostasis to maintain cellular functions and prevent disease. A central signaling molecule that integrates growth with metabolism is the mechanistic target of rapamycin (mTOR). mTOR is a protein kinase that responds to levels of nutrients and growth signals. mTOR forms two protein complexes, mTORC1, which is sensitive to rapamycin, and mTORC2, which is not directly inhibited by this drug. Rapamycin has facilitated the discovery of the various functions of mTORC1 in metabolism. Genetic models that disrupt either mTORC1 or mTORC2 have expanded our knowledge of their cellular, tissue, as well as systemic functions in metabolism. Nevertheless, our knowledge of the regulation and functions of mTORC2, particularly in metabolism, has lagged behind. Since mTOR is an important target for cancer, aging, and other metabolism-related pathologies, understanding the distinct and overlapping regulation and functions of the two mTOR complexes is vital for the development of more effective therapeutic strategies. This review discusses the key discoveries and recent findings on the regulation and metabolic functions of the mTOR complexes. We highlight findings from cancer models but also discuss other examples of the mTOR-mediated metabolic reprogramming occurring in stem and immune cells, type 2 diabetes/obesity, neurodegenerative disorders, and aging.
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Affiliation(s)
- Angelia Szwed
- Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey
| | - Eugene Kim
- Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey
| | - Estela Jacinto
- Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey
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Seoane-Collazo P, Romero-Picó A, Rial-Pensado E, Liñares-Pose L, Estévez-Salguero Á, Fernø J, Nogueiras R, Diéguez C, López M. κ-Opioid Signaling in the Lateral Hypothalamic Area Modulates Nicotine-Induced Negative Energy Balance. Int J Mol Sci 2021; 22:ijms22041515. [PMID: 33546289 PMCID: PMC7913331 DOI: 10.3390/ijms22041515] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/26/2021] [Accepted: 01/27/2021] [Indexed: 12/20/2022] Open
Abstract
Several studies have reported that nicotine, the main bioactive component of tobacco, exerts a marked negative energy balance. Apart from its anorectic action, nicotine also modulates energy expenditure, by regulating brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. These effects are mainly controlled at the central level by modulation of hypothalamic neuropeptide systems and energy sensors, such as AMP-activated protein kinase (AMPK). In this study, we aimed to investigate the kappa opioid receptor (κOR)/dynorphin signaling in the modulation of nicotine’s effects on energy balance. We found that body weight loss after nicotine treatment is associated with a down-regulation of the κOR endogenous ligand dynorphin precursor and with a marked reduction in κOR signaling and the p70 S6 kinase/ribosomal protein S6 (S6K/rpS6) pathway in the lateral hypothalamic area (LHA). The inhibition of these pathways by nicotine was completely blunted in κOR deficient mice, after central pharmacological blockade of κOR, and in rodents where κOR was genetically knocked down specifically in the LHA. Moreover, κOR-mediated nicotine effects on body weight do not depend on orexin. These data unravel a new central regulatory pathway modulating nicotine’s effects on energy balance.
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Affiliation(s)
- Patricia Seoane-Collazo
- Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain; (A.R.-P.); (E.R.-P.); (L.L.-P.); (Á.E.-S.); (R.N.); (C.D.)
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain
- Correspondence: (P.S.-C.); (M.L.)
| | - Amparo Romero-Picó
- Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain; (A.R.-P.); (E.R.-P.); (L.L.-P.); (Á.E.-S.); (R.N.); (C.D.)
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain
| | - Eva Rial-Pensado
- Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain; (A.R.-P.); (E.R.-P.); (L.L.-P.); (Á.E.-S.); (R.N.); (C.D.)
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain
| | - Laura Liñares-Pose
- Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain; (A.R.-P.); (E.R.-P.); (L.L.-P.); (Á.E.-S.); (R.N.); (C.D.)
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain
| | - Ánxela Estévez-Salguero
- Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain; (A.R.-P.); (E.R.-P.); (L.L.-P.); (Á.E.-S.); (R.N.); (C.D.)
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain
| | - Johan Fernø
- Hormone Laboratory, Haukeland University Hospital, N-5021 Bergen, Norway;
| | - Rubén Nogueiras
- Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain; (A.R.-P.); (E.R.-P.); (L.L.-P.); (Á.E.-S.); (R.N.); (C.D.)
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain
| | - Carlos Diéguez
- Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain; (A.R.-P.); (E.R.-P.); (L.L.-P.); (Á.E.-S.); (R.N.); (C.D.)
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain
| | - Miguel López
- Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain; (A.R.-P.); (E.R.-P.); (L.L.-P.); (Á.E.-S.); (R.N.); (C.D.)
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain
- Correspondence: (P.S.-C.); (M.L.)
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Abstract
Sensing and responding to changes in nutrient levels, including those of glucose, lipids, and amino acids, by the body is necessary for survival. Accordingly, perturbations in nutrient sensing are tightly linked with human pathologies, particularly metabolic diseases such as obesity, type 2 diabetes mellitus, and other complications of metabolic syndromes. The conventional view is that amino acids are fundamental elements for protein and peptide synthesis, while recent studies have revealed that amino acids are also important bioactive molecules that play key roles in signaling pathways and metabolic regulation. Different pathways that sense intracellular and extracellular levels of amino acids are integrated and coordinated at the organismal level, and, together, these pathways maintain whole metabolic homeostasis. In this review, we discuss the studies describing how important sensing signals respond to amino acid availability and how these sensing mechanisms modulate metabolic processes, including energy, glucose, and lipid metabolism. We further discuss whether dysregulation of amino acid sensing signals can be targeted to promote metabolic disorders, and discuss how to translate these mechanisms to treat human diseases. This review will help to enhance our overall understanding of the correlation between amino acid sensing and metabolic homeostasis, which have important implications for human health.
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Affiliation(s)
- Xiaoming Hu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Feifan Guo
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
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26
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Li K, Shen X, Qiu H, Zhao T, Ai K, Li C, Zhang Y, Li K, Duan M, Wei X, Yang J. S6K1/S6 axis-regulated lymphocyte activation is important for adaptive immune response of Nile tilapia. FISH & SHELLFISH IMMUNOLOGY 2020; 106:1120-1130. [PMID: 32971270 DOI: 10.1016/j.fsi.2020.09.031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 09/10/2020] [Accepted: 09/21/2020] [Indexed: 06/11/2023]
Abstract
Ribosomal protein S6 kinase beta-1 (S6K1) is a serine/threonine kinase downstream of the mechanistic target of rapamycin (mTOR) pathway, and plays crucial roles in immune regulation. Although remarkable progress has been achieved with a mouse model, how S6K1 regulates adaptive immunity is largely unknown in early vertebrates. In this study, we identified an S6K1 from Nile tilapia Oreochromis niloticus (OnS6K1), and further investigated its potential regulatory role on the adaptive immunity of this fish species. Both sequence and structure of OnS6K1 were highly conserved with its homologs from other vertebrates and invertebrates. OnS6K1 was widely expressed in immune tissues, and with a relative higher expression level in the liver, spleen and head kidney. At the adaptive immune stage of Nile tilapia that infected with Aeromonas hydrophila, mRNA expression of OnS6K1 and its downstream effector S6 was significantly up-regulated in spleen lymphocytes. Meanwhile, their phosphorylation level was also enhanced during this process, suggesting that S6K1/S6 axis participated in the primary response of anti-bacterial adaptive immunity in Nile tilapia. Furthermore, after spleen lymphocytes were activated by the T cell-specific mitogen PHA or lymphocytes agonist PMA in vitro, mRNA and phosphorylation levels of S6K1 were elevated, and phosphorylation of S6 was also enhanced. Once S6K1 activity was blocked by a specific inhibitor, both mRNA and phosphorylation levels of S6 were severely impaired. More importantly, blockade of S6K1/S6 axis reduced the expression of T cell activation marker IFN-γ and CD122 in PHA-activated spleen lymphocytes, indicating the essential role of S6K1/S6 axis in regulating T cell activation of Nile tilapia. Together, our study suggests that S6K1 and its effector S6 regulate lymphocyte activation of Nile tilapia, and in turn promote lymphocyte-mediated adaptive immunity. This study enriched the mechanism of adaptive immune response in teleost and provided useful clues to understand the evolution of adaptive immune system.
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Affiliation(s)
- Kunming Li
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Xiaotong Shen
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Hong Qiu
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Tianyu Zhao
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Kete Ai
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Cheng Li
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Yu Zhang
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Kang Li
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Ming Duan
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, Hubei, China.
| | - Xiumei Wei
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China.
| | - Jialong Yang
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China
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Peroxisome Proliferator-Activated Receptors and Caloric Restriction-Common Pathways Affecting Metabolism, Health, and Longevity. Cells 2020; 9:cells9071708. [PMID: 32708786 PMCID: PMC7407644 DOI: 10.3390/cells9071708] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/14/2020] [Accepted: 07/14/2020] [Indexed: 02/06/2023] Open
Abstract
Caloric restriction (CR) is a traditional but scientifically verified approach to promoting health and increasing lifespan. CR exerts its effects through multiple molecular pathways that trigger major metabolic adaptations. It influences key nutrient and energy-sensing pathways including mammalian target of rapamycin, Sirtuin 1, AMP-activated protein kinase, and insulin signaling, ultimately resulting in reductions in basic metabolic rate, inflammation, and oxidative stress, as well as increased autophagy and mitochondrial efficiency. CR shares multiple overlapping pathways with peroxisome proliferator-activated receptors (PPARs), particularly in energy metabolism and inflammation. Consequently, several lines of evidence suggest that PPARs might be indispensable for beneficial outcomes related to CR. In this review, we present the available evidence for the interconnection between CR and PPARs, highlighting their shared pathways and analyzing their interaction. We also discuss the possible contributions of PPARs to the effects of CR on whole organism outcomes.
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Seoane-Collazo P, Martínez-Sánchez N, Milbank E, Contreras C. Incendiary Leptin. Nutrients 2020; 12:nu12020472. [PMID: 32069871 PMCID: PMC7071158 DOI: 10.3390/nu12020472] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 02/06/2020] [Accepted: 02/08/2020] [Indexed: 02/08/2023] Open
Abstract
Leptin is a hormone released by adipose tissue that plays a key role in the control of energy homeostasis through its binding to leptin receptors (LepR), mainly expressed in the hypothalamus. Most scientific evidence points to leptin’s satiating effect being due to its dual capacity to promote the expression of anorexigenic neuropeptides and to reduce orexigenic expression in the hypothalamus. However, it has also been demonstrated that leptin can stimulate (i) thermogenesis in brown adipose tissue (BAT) and (ii) the browning of white adipose tissue (WAT). Since the demonstration of the importance of BAT in humans 10 years ago, its study has aroused great interest, mainly in the improvement of obesity-associated metabolic disorders through the induction of thermogenesis. Consequently, several strategies targeting BAT activation (mainly in rodent models) have demonstrated great potential to improve hyperlipidemias, hepatic steatosis, insulin resistance and weight gain, leading to an overall healthier metabolic profile. Here, we review the potential therapeutic ability of leptin to correct obesity and other metabolic disorders, not only through its satiating effect, but by also utilizing its thermogenic properties.
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Affiliation(s)
- Patricia Seoane-Collazo
- International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
- CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain;
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain
- Correspondence: (P.S.-C.); (N.M.-S.); (C.C.); Tel.: +81-298-533-301 (P.S.-C.); +34-913-941-650 (N.M.-S.); +44-01865285890 (C.C.)
| | - Noelia Martínez-Sánchez
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK
- Correspondence: (P.S.-C.); (N.M.-S.); (C.C.); Tel.: +81-298-533-301 (P.S.-C.); +34-913-941-650 (N.M.-S.); +44-01865285890 (C.C.)
| | - Edward Milbank
- CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain;
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain
| | - Cristina Contreras
- Department of Physiology, Pharmacy School, Complutense University of Madrid, 28040 Madrid, Spain
- Correspondence: (P.S.-C.); (N.M.-S.); (C.C.); Tel.: +81-298-533-301 (P.S.-C.); +34-913-941-650 (N.M.-S.); +44-01865285890 (C.C.)
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29
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Abstract
Leptin is a hormone that plays a major role as mediator of long-term regulation of energy balance, suppressing food intake, and stimulating weight loss. More recently, important physiological roles other than controlling appetite and energy expenditure have been suggested for leptin, including neuroendocrine, reparative, reproductive, and immune functions. These emerging peripheral roles let hypothesize that leptin can modulate also cancer progression. Indeed, many studies have demonstrated that elevated chronic serum concentrations of leptin, frequently seen in obese subjects, represent a stimulatory signal for tumor growth. Current knowledge indicates that also different non-tumoral cells resident in tumor microenvironment may respond to leptin creating a favorable soil for cancer cells. In addition, leptin is produced also within the tumor microenvironment creating the possibility for paracrine and autocrine action. In this review, we describe the main mechanisms that regulate peripheral leptin availability and how leptin can shape tumor microenvironment.
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30
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Liu H, Xu Y, Hu F. AMPK in the Ventromedial Nucleus of the Hypothalamus: A Key Regulator for Thermogenesis. Front Endocrinol (Lausanne) 2020; 11:578830. [PMID: 33071984 PMCID: PMC7538541 DOI: 10.3389/fendo.2020.578830] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 08/24/2020] [Indexed: 12/19/2022] Open
Abstract
Obesity has become a global health issue, but effective therapies remain very limited. Adaptive thermogenesis promotes weight loss by dissipating energy in the form of heat, thereby representing a promising target to counteract obesity. Notably, the regulation of thermogenesis is tightly orchestrated by complex neuronal networks, especially those in the hypothalamus. Recent evidence highlights the importance of adenosine monophosphate-activated protein kinase (AMPK) within the ventromedial nucleus of the hypothalamus (VMH) in modulating thermogenesis. Various molecules, such as GLP-1, leptin, estradiol, and thyroid hormones, have been reported to act on the VMH to inhibit AMPK, which subsequently increases thermogenesis through the activation of the sympathetic nervous system (SNS). In this review, we summarize the critical role of AMPK within the VMH in the control of energy balance, focusing on its contribution to thermogenesis and the associated mechanisms.
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Affiliation(s)
- Hailan Liu
- Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, China
- Department of Pediatrics, Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, United States
| | - Yong Xu
- Department of Pediatrics, Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, United States
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
| | - Fang Hu
- Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, China
- *Correspondence: Fang Hu
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31
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Tavares MR, Lemes SF, de Fante T, Saenz de Miera C, Pavan ICB, Bezerra RMN, Prada PO, Torsoni MA, Elias CF, Simabuco FM. Modulation of hypothalamic S6K1 and S6K2 alters feeding behavior and systemic glucose metabolism. J Endocrinol 2020; 244:71-82. [PMID: 31557728 PMCID: PMC8010582 DOI: 10.1530/joe-19-0364] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 09/26/2019] [Indexed: 11/08/2022]
Abstract
The mTOR/S6Ks signaling is one of the intracellular pathways important for metabolic control, acting both peripherally and centrally. In the hypothalamus, mTOR/S6Ks axis mediates the action of leptin and insulin and can modulate the expression of neuropeptides. We analyzed the role of different S6Ks isoforms in the hypothalamic regulation of metabolism. We observed decreased food intake and decreased expression of agouti-related peptide (AgRP) following intracerebroventricular (icv) injections of adenoviral-mediated overexpression of three different S6Ks isoforms. Moreover, mice overexpressing p70-S6K1 in undefined periventricular hypothalamic neurons presented changes in glucose metabolism, as an increase in gluconeogenesis. To further evaluate the hypothalamic role of a less-studied S6K isoform, p54-S6K2, we used a Cre-LoxP approach to specifically overexpress it in AgRP neurons. Our findings demonstrate the potential participation of S6K2 in AgRP neurons regulating feeding behavior.
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Affiliation(s)
- Mariana Rosolen Tavares
- Multidisciplinary Laboratory of Food and Health (LABMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
- Laboratory of Metabolic Disorders (LABDIME), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Simone Ferreira Lemes
- Laboratory of Metabolic Disorders (LABDIME), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Thais de Fante
- Laboratory of Metabolic Disorders (LABDIME), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Cristina Saenz de Miera
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA
| | - Isadora Carolina Betim Pavan
- Multidisciplinary Laboratory of Food and Health (LABMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
- Laboratory of Metabolic Disorders (LABDIME), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Rosangela Maria Neves Bezerra
- Multidisciplinary Laboratory of Food and Health (LABMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Patricia Oliveira Prada
- Laboratory of Molecular Research in Obesity (LABIMO), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Marcio Alberto Torsoni
- Laboratory of Metabolic Disorders (LABDIME), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Carol Fuzeti Elias
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA
| | - Fernando Moreira Simabuco
- Multidisciplinary Laboratory of Food and Health (LABMAS), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
- Laboratory of Metabolic Disorders (LABDIME), School of Applied Sciences (FCA), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
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32
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Fujita S, Honda K, Yamaguchi M, Fukuzo S, Saneyasu T, Kamisoyama H. Role of Insulin-like Growth Factor-1 in the Central Regulation of Feeding Behavior in Chicks. J Poult Sci 2019; 56:270-276. [PMID: 32055224 PMCID: PMC7005399 DOI: 10.2141/jpsa.0180127] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Accepted: 01/17/2019] [Indexed: 12/15/2022] Open
Abstract
Insulin-like growth factor-1 (IGF-1) is a key regulator of muscle development and metabolism in chickens. Recently, we have demonstrated that intracerebroventricular administration of IGF-1 significantly decreased food intake in broiler chicks. However, the molecular mechanisms underlying the IGF-1-induced anorexia and the anorexigenic effect of IGF-1 in different strains of commercial chicks have not been investigated. Neuropeptide Y (NPY, a hypothalamic orexigenic neuropeptide), agouti-related protein (AgRP, a hypothalamic orexigenic neuropeptide), and proopiomelanocortin (POMC, the precursor of hypothalamic anorexigenic neuropeptides) play important roles in the regulation of food intake in both mammals and chickens. Evidence shows that several cell signaling pathways in the hypothalamus are involved in regulating the feeding behavior of mammals. In the present study, we first investigated the effects of IGF-1 on the expression of appetite-regulating neuropeptides and phosphorylation of signaling molecules in the hypothalamus of broiler chicks. Intracerebroventricular administration of IGF-1 significantly increased the mRNA levels of POMC, whereas the mRNA levels of NPY and AgRP were not significantly altered. IGF-1 also significantly induced the phosphorylation of v-Akt murine thymoma viral oncogene homolog 1 (AKT) in the hypothalamus of chicks, but did not influence the phosphorylation of forkhead box O1, S6 protein, AMP-activated protein kinase, and extracellular signal-regulated kinase 1/2. We also compared the effect of IGF-1 on food intake in broiler chicks (a hyperphagic strain of chickens) and layer chicks. Results demonstrated that the threshold of IGF-1-induced anorexia in broiler chicks was higher than that in layer chicks. Our observations suggest that hypothalamic POMC and AKT may be involved in the IGF-1-induced anorexigenic pathway and that high threshold of IGF-1-induced anorexia in broiler chicks might be one of the causes of hyperphagia in broiler chicks. Overall, it appears that IGF-1 plays important roles in the central regulation of feeding behavior in chicks.
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Affiliation(s)
- Shoichi Fujita
- Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan
| | - Kazuhisa Honda
- Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan
| | - Mika Yamaguchi
- Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan
| | - Satoshi Fukuzo
- Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan
| | - Takaoki Saneyasu
- Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan
| | - Hiroshi Kamisoyama
- Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan
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mTORC1 and CB1 receptor signaling regulate excitatory glutamatergic inputs onto the hypothalamic paraventricular nucleus in response to energy availability. Mol Metab 2019; 28:151-159. [PMID: 31420305 PMCID: PMC6822143 DOI: 10.1016/j.molmet.2019.08.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 07/31/2019] [Accepted: 08/02/2019] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVE The hypothalamic paraventricular nucleus (PVN) is a key target of the melanocortin system, which orchestrates behavioral and metabolic responses depending on energy availability. The mechanistic target of rapamycin complex 1 (mTORC1) and the endocannabinoid type 1 receptor (CB1R) pathways are two key signaling systems involved in the regulation of energy balance whose activity closely depends upon energy availability. Here we tested the hypothesis that modulation of mTORC1 and CB1R signaling regulates excitatory glutamatergic inputs onto the PVN. METHODS Patch-clamp recordings in C57BL/6J mice, in mice lacking the mTORC1 component Rptor or CB1R in pro-opio-melanocortin (POMC) neurons, combined with pharmacology targeting mTORC1, the melanocortin receptor type 4 (MC4R), or the endocannabinoid system under chow or a hypercaloric diet. RESULTS Acute pharmacological inhibition of mTORC1 in C57BL/6J mice decreased glutamatergic inputs onto the PVN via a mechanism requiring modulation of MC4R, endocannabinoid 2-AG mobilization by PVN parvocellular neurons, and retrograde activation of presynaptic CB1R. Further electrophysiology studies using mice lacking mTORC1 activity or CB1R in POMC neurons indicated that the observed effects involved mTORC1 and CB1R-dependent regulation of glutamate release from POMC neurons. Finally, energy surfeit caused by hypercaloric high-fat diet feeding, rapidly and time-dependently altered the glutamatergic inputs onto parvocellular neurons and the ability of mTORC1 and CB1R signaling to modulate such excitatory activity. CONCLUSIONS These findings pinpoint the relationship between mTORC1 and endocannabinoid-CB1R signaling in the regulation of the POMC-mediated glutamatergic inputs onto PVN parvocellular neurons and its rapid alteration in conditions favoring the development of obesity.
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Folgueira C, Beiroa D, Porteiro B, Duquenne M, Puighermanal E, Fondevila MF, Barja-Fernández S, Gallego R, Hernández-Bautista R, Castelao C, Senra A, Seoane P, Gómez N, Aguiar P, Guallar D, Fidalgo M, Romero-Pico A, Adan R, Blouet C, Labandeira-García JL, Jeanrenaud F, Kallo I, Liposits Z, Salvador J, Prevot V, Dieguez C, Lopez M, Valjent E, Frühbeck G, Seoane LM, Nogueiras R. Hypothalamic dopamine signaling regulates brown fat thermogenesis. Nat Metab 2019; 1:811-829. [PMID: 31579887 PMCID: PMC6774781 DOI: 10.1038/s42255-019-0099-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Dopamine signaling is a crucial part of the brain reward system and can affect feeding behavior. Dopamine receptors are also expressed in the hypothalamus, which is known to control energy metabolism in peripheral tissues. Here we show that pharmacological or chemogenetic stimulation of dopamine receptor 2 (D2R) expressing cells in the lateral hypothalamic area (LHA) and the zona incerta (ZI) decreases body weight and stimulates brown fat activity in rodents in a feeding-independent manner. LHA/ZI D2R stimulation requires an intact sympathetic nervous system and orexin system to exert its action and involves inhibition of PI3K in the LHA/ZI. We further demonstrate that, as early as 3 months after onset of treatment, patients treated with the D2R agonist cabergoline experience an increase in energy expenditure that persists for one year, leading to total body weight and fat loss through a prolactin-independent mechanism. Our results may provide a mechanistic explanation for how clinically used D2R agonists act in the CNS to regulate energy balance.
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Affiliation(s)
- Cintia Folgueira
- Grupo Fisiopatología Endocrina, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo. Hospitalario Universitario de Santiago (CHUS/SERGAS), Instituto de Investigación Sanitaria, Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
- CIMUS, Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
| | - Daniel Beiroa
- CIMUS, Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
| | - Begoña Porteiro
- CIMUS, Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
| | - Manon Duquenne
- Jean-Pierre Aubert Research Center (JPArc), Laboratory of Development and Plasticity of the Neuroendocrine Brain, Inserm UMR-S 1172, Lille, France
| | | | - Marcos F Fondevila
- CIMUS, Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
| | - Silvia Barja-Fernández
- Grupo Fisiopatología Endocrina, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo. Hospitalario Universitario de Santiago (CHUS/SERGAS), Instituto de Investigación Sanitaria, Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
| | - Rosalia Gallego
- Department of Morphological Sciences, School of Medicine, University of Santiago de Compostela, S. Francisco s/n, 15782 Santiago de Compostela (A Coruña), Spain
| | - René Hernández-Bautista
- CIMUS, Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
| | - Cecilia Castelao
- Grupo Fisiopatología Endocrina, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo. Hospitalario Universitario de Santiago (CHUS/SERGAS), Instituto de Investigación Sanitaria, Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
| | - Ana Senra
- CIMUS, Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
| | - Patricia Seoane
- CIMUS, Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
| | - Noemi Gómez
- Molecular Imaging Group, Department of Psychiatry, Radiology and Public Health, Faculty of Medicine Universidade de Santiago de Compostela (USC), Santiago de Compostela 15782 Spain; Molecular Imaging Group. Health Research Institute of Santiago de Compostela (IDIS). Travesía da Choupana s/n Santiago de Compostela. Zip Code: 15706. Spain; Nuclear Medicine Department University Clinical Hospital Santiago de Compostela (SERGAS) (CHUS), Travesía Choupana s/n. Santiago de Compostela 15706 Spain
| | - Pablo Aguiar
- Molecular Imaging Group, Department of Psychiatry, Radiology and Public Health, Faculty of Medicine Universidade de Santiago de Compostela (USC), Santiago de Compostela 15782 Spain; Molecular Imaging Group. Health Research Institute of Santiago de Compostela (IDIS). Travesía da Choupana s/n Santiago de Compostela. Zip Code: 15706. Spain; Nuclear Medicine Department University Clinical Hospital Santiago de Compostela (SERGAS) (CHUS), Travesía Choupana s/n. Santiago de Compostela 15706 Spain
| | - Diana Guallar
- CIMUS, Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
| | - Miguel Fidalgo
- CIMUS, Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
| | - Amparo Romero-Pico
- CIMUS, Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
| | - Roger Adan
- Brain Center Rudolf Magnus, Department of Neuroscience and Pharmacology, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands
| | - Clemence Blouet
- MRC Metabolic Disease Unit. Institute of Metabolic Science. University of Cambridge, UK
| | - Jose Luís Labandeira-García
- CIMUS, Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
- Networking Research Center on Neurodegenerative Diseases, CIBERNED, Madrid, Spain
| | - Françoise Jeanrenaud
- Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Imre Kallo
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, HAS, 1083, Budapest, Hungary
| | - Zsolt Liposits
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, HAS, 1083, Budapest, Hungary
| | - Javier Salvador
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra & IdiSNA, Pamplona, Spain
| | - Vincent Prevot
- Jean-Pierre Aubert Research Center (JPArc), Laboratory of Development and Plasticity of the Neuroendocrine Brain, Inserm UMR-S 1172, Lille, France
| | - Carlos Dieguez
- CIMUS, Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
| | - Miguel Lopez
- CIMUS, Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
| | - Emmanuel Valjent
- IGF, Inserm, CNRS, Univ. Montpellier, F-34094 Montpellier, France
| | - Gema Frühbeck
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra & IdiSNA, Pamplona, Spain
| | - Luisa M Seoane
- Grupo Fisiopatología Endocrina, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo. Hospitalario Universitario de Santiago (CHUS/SERGAS), Instituto de Investigación Sanitaria, Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
| | - Ruben Nogueiras
- CIMUS, Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
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Papadopoli D, Boulay K, Kazak L, Pollak M, Mallette FA, Topisirovic I, Hulea L. mTOR as a central regulator of lifespan and aging. F1000Res 2019; 8:F1000 Faculty Rev-998. [PMID: 31316753 PMCID: PMC6611156 DOI: 10.12688/f1000research.17196.1] [Citation(s) in RCA: 237] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/20/2019] [Indexed: 12/17/2022] Open
Abstract
The mammalian/mechanistic target of rapamycin (mTOR) is a key component of cellular metabolism that integrates nutrient sensing with cellular processes that fuel cell growth and proliferation. Although the involvement of the mTOR pathway in regulating life span and aging has been studied extensively in the last decade, the underpinning mechanisms remain elusive. In this review, we highlight the emerging insights that link mTOR to various processes related to aging, such as nutrient sensing, maintenance of proteostasis, autophagy, mitochondrial dysfunction, cellular senescence, and decline in stem cell function.
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Affiliation(s)
- David Papadopoli
- Gerald Bronfman Department of Oncology, McGill University, 5100 de Maisonneuve Blvd. West, Suite 720, Montréal, QC, H4A 3T2, Canada
- Lady Davis Institute, SMBD JGH, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, QC, H3T 1E2, Canada
| | - Karine Boulay
- Lady Davis Institute, SMBD JGH, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, QC, H3T 1E2, Canada
- Maisonneuve-Rosemont Hospital Research Centre, 5415 Assumption Blvd, Montréal, QC, H1T 2M4, Canada
- Département de Biochimie et Médecine Moléculaire, Université de Montréal, CP 6128, Succursale Centre-Ville, Montréal, QC, H3C 3J7, Canada
| | - Lawrence Kazak
- Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montréal, QC, H3G 1Y6, Canada
- Goodman Cancer Research Centre, 1160 Pine Avenue West, Montréal, QC, H3A 1A3, Canada
| | - Michael Pollak
- Gerald Bronfman Department of Oncology, McGill University, 5100 de Maisonneuve Blvd. West, Suite 720, Montréal, QC, H4A 3T2, Canada
- Lady Davis Institute, SMBD JGH, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, QC, H3T 1E2, Canada
- Goodman Cancer Research Centre, 1160 Pine Avenue West, Montréal, QC, H3A 1A3, Canada
- Department of Experimental Medicine, McGill University, 845 Sherbrooke Street West, Montréal, QC, H3A 0G4, Canada
| | - Frédérick A. Mallette
- Maisonneuve-Rosemont Hospital Research Centre, 5415 Assumption Blvd, Montréal, QC, H1T 2M4, Canada
- Département de Biochimie et Médecine Moléculaire, Université de Montréal, CP 6128, Succursale Centre-Ville, Montréal, QC, H3C 3J7, Canada
- Département de Médecine, Université de Montréal, CP 6128, Succursale Centre-Ville, Montréal, QC, H3C 3J7, Canada
| | - Ivan Topisirovic
- Gerald Bronfman Department of Oncology, McGill University, 5100 de Maisonneuve Blvd. West, Suite 720, Montréal, QC, H4A 3T2, Canada
- Lady Davis Institute, SMBD JGH, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, QC, H3T 1E2, Canada
- Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montréal, QC, H3G 1Y6, Canada
- Department of Experimental Medicine, McGill University, 845 Sherbrooke Street West, Montréal, QC, H3A 0G4, Canada
| | - Laura Hulea
- Maisonneuve-Rosemont Hospital Research Centre, 5415 Assumption Blvd, Montréal, QC, H1T 2M4, Canada
- Département de Biochimie et Médecine Moléculaire, Université de Montréal, CP 6128, Succursale Centre-Ville, Montréal, QC, H3C 3J7, Canada
- Département de Médecine, Université de Montréal, CP 6128, Succursale Centre-Ville, Montréal, QC, H3C 3J7, Canada
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mTOR Signaling Pathway in Cancer Targets Photodynamic Therapy In Vitro. Cells 2019; 8:cells8050431. [PMID: 31075885 PMCID: PMC6563036 DOI: 10.3390/cells8050431] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 04/22/2019] [Accepted: 04/30/2019] [Indexed: 01/03/2023] Open
Abstract
The Mechanistic or Mammalian Target of Rapamycin (mTOR) is a major signaling pathway in eukaryotic cells belonging to the P13K-related kinase family of the serine/threonine protein kinase. It has been established that mTOR plays a central role in cellular processes and implicated in various cancers, diabetes, and in the aging process with very poor prognosis. Inhibition of the mTOR pathway in the cells may improve the therapeutic index in cancer treatment. Photodynamic therapy (PDT) has been established to selectively eradicate neoplasia at clearly delineated malignant lesions. This review highlights recent advances in understanding the role or regulation of mTOR in cancer therapy. It also discusses how mTOR currently contributes to cancer as well as future perspectives on targeting mTOR therapeutically in cancer in vitro.
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Larson KR, Chaffin ATB, Goodson ML, Fang Y, Ryan KK. Fibroblast Growth Factor-21 Controls Dietary Protein Intake in Male Mice. Endocrinology 2019; 160:1069-1080. [PMID: 30802283 PMCID: PMC6469953 DOI: 10.1210/en.2018-01056] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 02/20/2019] [Indexed: 12/14/2022]
Abstract
Whereas carbohydrates and lipids are stored as glycogen and fat, there is no analogous inert storage form of protein. Therefore, continuous adjustments in feeding behavior are needed to match amino acid supply to ongoing physiologic need. Neuroendocrine mechanisms facilitating this behavioral control of protein and amino acid homeostasis remain unclear. The hepatokine fibroblast growth factor-21 (FGF21) is well positioned for such a role, as it is robustly secreted in response to protein and/or amino acid deficit. In this study, we tested the hypothesis that FGF21 feeds back at its receptors in the nervous system to shift macronutrient selection toward protein. In a series of behavioral tests, we isolated the effect of FGF21 to influence consumption of protein, fat, and carbohydrate in male mice. First, we used a three-choice pure macronutrient-diet paradigm. In response to FGF21, mice increased consumption of protein while reducing carbohydrate intake, with no effect on fat intake. Next, to determine whether protein or carbohydrate was the primary-regulated nutrient, we used a sequence of two-choice experiments to isolate the effect of FGF21 on preference for each macronutrient. Sweetness was well controlled by holding sucrose constant across the diets. Under these conditions, FGF21 increased protein intake, and this was offset by reducing the consumption of either carbohydrate or fat. When protein was held constant, FGF21 had no effect on macronutrient intake. Lastly, the effect of FGF21 to increase protein intake required the presence of its co-receptor, β-klotho, in neurons. Taken together, these findings point to a novel liver→nervous system pathway underlying the regulation of dietary protein intake via FGF21.
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Affiliation(s)
- Karlton R Larson
- Department of Neurobiology, Physiology, and Behavior, College of Biological Sciences, University of California, Davis, Davis, California
| | - Aki T-B Chaffin
- Department of Neurobiology, Physiology, and Behavior, College of Biological Sciences, University of California, Davis, Davis, California
| | - Michael L Goodson
- Department of Neurobiology, Physiology, and Behavior, College of Biological Sciences, University of California, Davis, Davis, California
| | - Yanbin Fang
- Department of Neurobiology, Physiology, and Behavior, College of Biological Sciences, University of California, Davis, Davis, California
| | - Karen K Ryan
- Department of Neurobiology, Physiology, and Behavior, College of Biological Sciences, University of California, Davis, Davis, California
- Correspondence: Karen K. Ryan, PhD, Department of Neurobiology, Physiology, and Behavior, University of California, Davis, 1 Shields Avenue, 196 Briggs Hall, Davis, California 95616. E-mail:
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Yang Y, van der Klaauw AA, Zhu L, Cacciottolo TM, He Y, Stadler LKJ, Wang C, Xu P, Saito K, Hinton A, Yan X, Keogh JM, Henning E, Banton MC, Hendricks AE, Bochukova EG, Mistry V, Lawler KL, Liao L, Xu J, O'Rahilly S, Tong Q, Inês Barroso, O'Malley BW, Farooqi IS, Xu Y. Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis. Nat Commun 2019; 10:1718. [PMID: 30979869 PMCID: PMC6461669 DOI: 10.1038/s41467-019-08737-6] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 01/21/2019] [Indexed: 12/04/2022] Open
Abstract
Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here, we show that Steroid Receptor Coactivator-1 (SRC-1) interacts with a target of leptin receptor activation, phosphorylated STAT3, to potentiate Pomc transcription. Deletion of SRC-1 in Pomc neurons in mice attenuates their depolarization by leptin, decreases Pomc expression and increases food intake leading to high-fat diet-induced obesity. In humans, fifteen rare heterozygous variants in SRC-1 found in severely obese individuals impair leptin-mediated Pomc reporter activity in cells, whilst four variants found in non-obese controls do not. In a knock-in mouse model of a loss of function human variant (SRC-1L1376P), leptin-induced depolarization of Pomc neurons and Pomc expression are significantly reduced, and food intake and body weight are increased. In summary, we demonstrate that SRC-1 modulates the function of hypothalamic Pomc neurons, and suggest that targeting SRC-1 may represent a useful therapeutic strategy for weight loss.
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Affiliation(s)
- Yongjie Yang
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
| | - Agatha A van der Klaauw
- University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Liangru Zhu
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, 430022, China
| | - Tessa M Cacciottolo
- University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Yanlin He
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
| | - Lukas K J Stadler
- University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Chunmei Wang
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
| | - Pingwen Xu
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
| | - Kenji Saito
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
| | - Antentor Hinton
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
| | - Xiaofeng Yan
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
| | - Julia M Keogh
- University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Elana Henning
- University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Matthew C Banton
- University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Audrey E Hendricks
- Wellcome Sanger Institute, Cambridge, CB10 1SA, UK
- Mathematical and Statistical Sciences Department, University of Colorado - Denver, Denver, CO, 80204, USA
| | - Elena G Bochukova
- University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Vanisha Mistry
- University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Katherine L Lawler
- University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Lan Liao
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Jianming Xu
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Stephen O'Rahilly
- University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Qingchun Tong
- Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | | | - Inês Barroso
- Wellcome Sanger Institute, Cambridge, CB10 1SA, UK
| | - Bert W O'Malley
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - I Sadaf Farooqi
- University of Cambridge Metabolic Research Laboratories, and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
| | - Yong Xu
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
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Molecular Mechanisms of Hypothalamic Insulin Resistance. Int J Mol Sci 2019; 20:ijms20061317. [PMID: 30875909 PMCID: PMC6471380 DOI: 10.3390/ijms20061317] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/07/2019] [Accepted: 03/13/2019] [Indexed: 02/06/2023] Open
Abstract
Insulin exists in the central nervous system, where it executes two important functions in the hypothalamus: the suppression of food intake and the improvement of glucose metabolism. Recent studies have shown that both are exerted robustly in rodents and humans. If intact, these functions exert beneficial effects on obesity and diabetes, respectively. Disruption of both occurs due to a condition known as hypothalamic insulin resistance, which is caused by obesity and the overconsumption of saturated fat. An enormous volume of literature addresses the molecular mechanisms of hypothalamic insulin resistance. IKKβ and JNK are major players in the inflammation pathway, which is activated by saturated fatty acids that induce hypothalamic insulin resistance. Two major tyrosine phosphatases, PTP-1B and TCPTP, are upregulated in chronic overeating. They dephosphorylate the insulin receptor and insulin receptor substrate proteins, resulting in hypothalamic insulin resistance. Prolonged hyperinsulinemia with excessive nutrition activates the mTOR/S6 kinase pathway, thereby enhancing IRS-1 serine phosphorylation to induce hypothalamic insulin resistance. Other mechanisms associated with this condition include hypothalamic gliosis and disturbed insulin transport into the central nervous system. Unveiling the precise molecular mechanisms involved in hypothalamic insulin resistance is important for developing new ways of treating obesity and type 2 diabetes.
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Cellular Metabolic Regulation in the Differentiation and Function of Regulatory T Cells. Cells 2019; 8:cells8020188. [PMID: 30795546 PMCID: PMC6407031 DOI: 10.3390/cells8020188] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 02/17/2019] [Accepted: 02/20/2019] [Indexed: 12/29/2022] Open
Abstract
Regulatory T cells (Tregs) are essential for maintaining immune tolerance and preventing autoimmune and inflammatory diseases. The activity and function of Tregs are in large part determined by various intracellular metabolic processes. Recent findings have focused on how intracellular metabolism can shape the development, trafficking, and function of Tregs. In this review, we summarize and discuss current research that reveals how distinct metabolic pathways modulate Tregs differentiation, phenotype stabilization, and function. These advances highlight numerous opportunities to alter Tregs frequency and function in physiopathologic conditions via metabolic manipulation and have important translational implications.
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Caron A, Briscoe DM, Richard D, Laplante M. DEPTOR at the Nexus of Cancer, Metabolism, and Immunity. Physiol Rev 2018; 98:1765-1803. [PMID: 29897294 DOI: 10.1152/physrev.00064.2017] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
DEP domain-containing mechanistic target of rapamycin (mTOR)-interacting protein (DEPTOR) is an important modulator of mTOR, a kinase at the center of two important protein complexes named mTORC1 and mTORC2. These highly studied complexes play essential roles in regulating growth, metabolism, and immunity in response to mitogens, nutrients, and cytokines. Defects in mTOR signaling have been associated with the development of many diseases, including cancer and diabetes, and approaches aiming at modulating mTOR activity are envisioned as an attractive strategy to improve human health. DEPTOR interaction with mTOR represses its kinase activity and rewires the mTOR signaling pathway. Over the last years, several studies have revealed key roles for DEPTOR in numerous biological and pathological processes. Here, we provide the current state of the knowledge regarding the cellular and physiological functions of DEPTOR by focusing on its impact on the mTOR pathway and its role in promoting health and disease.
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Affiliation(s)
- Alexandre Caron
- Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center , Dallas, Texas ; Transplant Research Program, Boston Children's Hospital , Boston, Massachusetts ; Department of Pediatrics, Harvard Medical School , Boston, Massachusetts ; Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Faculté de Médecine, Université Laval , Québec , Canada ; and Centre de Recherche sur le Cancer de l'Université Laval, Université Laval , Québec , Canada
| | - David M Briscoe
- Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center , Dallas, Texas ; Transplant Research Program, Boston Children's Hospital , Boston, Massachusetts ; Department of Pediatrics, Harvard Medical School , Boston, Massachusetts ; Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Faculté de Médecine, Université Laval , Québec , Canada ; and Centre de Recherche sur le Cancer de l'Université Laval, Université Laval , Québec , Canada
| | - Denis Richard
- Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center , Dallas, Texas ; Transplant Research Program, Boston Children's Hospital , Boston, Massachusetts ; Department of Pediatrics, Harvard Medical School , Boston, Massachusetts ; Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Faculté de Médecine, Université Laval , Québec , Canada ; and Centre de Recherche sur le Cancer de l'Université Laval, Université Laval , Québec , Canada
| | - Mathieu Laplante
- Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center , Dallas, Texas ; Transplant Research Program, Boston Children's Hospital , Boston, Massachusetts ; Department of Pediatrics, Harvard Medical School , Boston, Massachusetts ; Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Faculté de Médecine, Université Laval , Québec , Canada ; and Centre de Recherche sur le Cancer de l'Université Laval, Université Laval , Québec , Canada
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Insights into leptin signaling and male reproductive health: the missing link between overweight and subfertility? Biochem J 2018; 475:3535-3560. [DOI: 10.1042/bcj20180631] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 09/28/2018] [Accepted: 10/19/2018] [Indexed: 12/24/2022]
Abstract
Obesity stands as one of the greatest healthcare challenges of the 21st century. Obesity in reproductive-age men is ever more frequent and is reaching upsetting levels. At the same time, fertility has taken an inverse direction and is decreasing, leading to an increased demand for fertility treatments. In half of infertile couples, there is a male factor alone or combined with a female factor. Furthermore, male fertility parameters such as sperm count and concentration went on a downward spiral during the last few decades and are now approaching the minimum levels established to achieve successful fertilization. Hence, the hypothesis that obesity and deleterious effects in male reproductive health, as reflected in deterioration of sperm parameters, are somehow related is tempting. Most often, overweight and obese individuals present leptin levels directly proportional to the increased fat mass. Leptin, besides the well-described central hypothalamic effects, also acts in several peripheral organs, including the testes, thus highlighting a possible regulatory role in male reproductive function. In the last years, research focusing on leptin effects in male reproductive function has unveiled additional roles and molecular mechanisms of action for this hormone at the testicular level. Herein, we summarize the novel molecular signals linking metabolism and male reproductive function with a focus on leptin signaling, mitochondria and relevant pathways for the nutritional support of spermatogenesis.
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Nam KH, Yi SA, Lee J, Lee MG, Park JH, Oh H, Lee J, Park JW, Han JW. Eudesmin impairs adipogenic differentiation via inhibition of S6K1 signaling pathway. Biochem Biophys Res Commun 2018; 505:1148-1153. [PMID: 30316515 DOI: 10.1016/j.bbrc.2018.09.188] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 09/29/2018] [Indexed: 12/25/2022]
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Leptin Signaling in the Control of Metabolism and Appetite: Lessons from Animal Models. J Mol Neurosci 2018; 66:390-402. [PMID: 30284225 DOI: 10.1007/s12031-018-1185-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 09/24/2018] [Indexed: 12/15/2022]
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González-García I, Martínez de Morentin PB, Estévez-Salguero Á, Contreras C, Romero-Picó A, Fernø J, Nogueiras R, Diéguez C, Tena-Sempere M, Tovar S, López M. mTOR signaling in the arcuate nucleus of the hypothalamus mediates the anorectic action of estradiol. J Endocrinol 2018; 238:177-186. [PMID: 29914932 PMCID: PMC6055430 DOI: 10.1530/joe-18-0190] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Accepted: 06/18/2018] [Indexed: 12/15/2022]
Abstract
Current evidence suggests that estradiol (E2), the main ovarian steroid, modulates energy balance by regulating both feeding and energy expenditure at the central level, through the energy sensor AMP-activated protein kinase (AMPK). We hypothesized that the hypothalamic mechanistic target of rapamycin (mTOR) pathway, a well-established nutrient sensor and modulator of appetite and puberty, could also mediate the anorectic effect of E2. Our data showed that ovariectomy (OVX) elicited a marked downregulation of the mTOR signaling in the arcuate nucleus of the hypothalamus (ARC), an effect that was reversed by either E2 replacement or central estrogen receptor alpha (ERα) agonism. The significance of this molecular signaling was given by the genetic inactivation of S6 kinase B1 (S6K1, a key downstream mTOR effector) in the ARC, which prevented the E2-induced hypophagia and weight loss. Overall, these data indicate that E2 induces hypophagia through modulation of mTOR pathway in the ARC.
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Affiliation(s)
- Ismael González-García
- Department of PhysiologyCiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)Santiago de Compostela, Spain
| | - Pablo B Martínez de Morentin
- Department of PhysiologyCiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)Santiago de Compostela, Spain
| | - Ánxela Estévez-Salguero
- Department of PhysiologyCiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)Santiago de Compostela, Spain
| | - Cristina Contreras
- Department of PhysiologyCiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)Santiago de Compostela, Spain
| | - Amparo Romero-Picó
- Department of PhysiologyCiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)Santiago de Compostela, Spain
| | - Johan Fernø
- Hormone LaboratoryHaukeland University Hospital, Bergen, Norway
- KG Jebsen Center for Diabetes ResearchDepartment of Clinical Science, University of Bergen, Bergen, Norway
| | - Rubén Nogueiras
- Department of PhysiologyCiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)Santiago de Compostela, Spain
| | - Carlos Diéguez
- Department of PhysiologyCiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)Santiago de Compostela, Spain
| | - Manuel Tena-Sempere
- Department of Cell BiologyPhysiology and Immunology, University of Córdoba, Córdoba, Spain
- Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Reina SofíaCórdoba, Spain
- FiDiPro ProgramUniversity of Turku, Turku, Finland
| | - Sulay Tovar
- Department of PhysiologyCiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)Santiago de Compostela, Spain
| | - Miguel López
- Department of PhysiologyCiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)Santiago de Compostela, Spain
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Emerging Concepts in Brain Glucose Metabolic Functions: From Glucose Sensing to How the Sweet Taste of Glucose Regulates Its Own Metabolism in Astrocytes and Neurons. Neuromolecular Med 2018; 20:281-300. [DOI: 10.1007/s12017-018-8503-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 07/13/2018] [Indexed: 12/16/2022]
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Role of mTOR in Glucose and Lipid Metabolism. Int J Mol Sci 2018; 19:ijms19072043. [PMID: 30011848 PMCID: PMC6073766 DOI: 10.3390/ijms19072043] [Citation(s) in RCA: 176] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 07/10/2018] [Accepted: 07/11/2018] [Indexed: 02/06/2023] Open
Abstract
The mammalian target of rapamycin, mTOR is the master regulator of a cell’s growth and metabolic state in response to nutrients, growth factors and many extracellular cues. Its dysregulation leads to a number of metabolic pathological conditions, including obesity and type 2 diabetes. Here, we review recent findings on the role of mTOR in major metabolic organs, such as adipose tissues, liver, muscle, pancreas and brain. And their potentials as the mTOR related pharmacological targets will be also discussed.
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André C, Catania C, Remus-Borel J, Ladeveze E, Leste-Lasserre T, Mazier W, Binder E, Gonzales D, Clark S, Guzman-Quevedo O, Abrous DN, Layé S, Cota D. mTORC1 pathway disruption abrogates the effects of the ciliary neurotrophic factor on energy balance and hypothalamic neuroinflammation. Brain Behav Immun 2018; 70:325-334. [PMID: 29548998 DOI: 10.1016/j.bbi.2018.03.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 03/02/2018] [Accepted: 03/12/2018] [Indexed: 11/19/2022] Open
Abstract
Ciliary neurotrophic factor (CNTF) potently decreases food intake and body weight in diet-induced obese mice by acting through neuronal circuits and pathways located in the arcuate nucleus (ARC) of the hypothalamus. CNTF also exerts pro-inflammatory actions within the brain. Here we tested whether CNTF modifies energy balance by inducing inflammatory responses in the ARC and whether these effects depend upon the mechanistic target of rapamycin complex 1 (mTORC1) pathway, which regulates both energy metabolism and inflammation. To this purpose, chow- and high fat diet (HFD)- fed mice lacking the S6 kinase 1 (S6K1-/-), a downstream target of mTORC1, and their wild-type (WT) littermates received 12 days continuous intracerebroventricular (icv) infusion of the CNTF analogue axokine (CNTFAx15). Behavioral, metabolic and molecular effects were evaluated. Central chronic administration of CNTFAx15 decreased body weight and feed efficiency in WT mice only, when fed HFD, but not chow. These metabolic effects correlated with increased number of iba-1 positive microglia specifically in the ARC and were accompanied by significant increases of IL-1β and TNF-α mRNA expression in the hypothalamus. Hypothalamic iNOS and SOCS3 mRNA, molecular markers of pro-inflammatory response, were also increased by CNTFAx15. All these changes were absent in S6K1-/- mice. This study reveals that CNTFAx15 requires a functional S6K1 to modulate energy balance and hypothalamic inflammation in a diet-dependent fashion. Further investigations should determine whether S6K1 is a suitable target for the treatment of pathologies characterized by a high neuroinflammatory state.
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Affiliation(s)
- Caroline André
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France
| | - Caterina Catania
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France
| | - Julie Remus-Borel
- INRA, Nutrition et Neurobiologie Intégrée, UMR 1286, F-33076 Bordeaux, France; University of Bordeaux, Nutrition et Neurobiologie Intégrée, UMR 1286, F-33076 Bordeaux, France
| | - Elodie Ladeveze
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France
| | - Thierry Leste-Lasserre
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France
| | - Wilfrid Mazier
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France
| | - Elke Binder
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France
| | - Delphine Gonzales
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France
| | - Samantha Clark
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France
| | - Omar Guzman-Quevedo
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France
| | - Djoher Nora Abrous
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France
| | - Sophie Layé
- INRA, Nutrition et Neurobiologie Intégrée, UMR 1286, F-33076 Bordeaux, France; University of Bordeaux, Nutrition et Neurobiologie Intégrée, UMR 1286, F-33076 Bordeaux, France
| | - Daniela Cota
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France.
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Haissaguerre M, Ferrière A, Simon V, Saucisse N, Dupuy N, André C, Clark S, Guzman-Quevedo O, Tabarin A, Cota D. mTORC1-dependent increase in oxidative metabolism in POMC neurons regulates food intake and action of leptin. Mol Metab 2018; 12:98-106. [PMID: 29699927 PMCID: PMC6001919 DOI: 10.1016/j.molmet.2018.04.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 04/05/2018] [Accepted: 04/07/2018] [Indexed: 01/19/2023] Open
Abstract
OBJECTIVE Nutrient availability modulates reactive oxygen species (ROS) production in the hypothalamus. In turn, ROS regulate hypothalamic neuronal activity and feeding behavior. The mechanistic target of rapamycin complex 1 (mTORC1) pathway is an important cellular integrator of the action of nutrients and hormones. Here we tested the hypothesis that modulation of mTORC1 activity, particularly in Proopiomelanocortin (POMC)-expressing neurons, mediates the cellular and behavioral effects of ROS. METHODS C57BL/6J mice or controls and their knockout (KO) littermates deficient either for the mTORC1 downstream target 70-kDa ribosomal protein S6 kinase 1 (S6K1) or for the mTORC1 component Rptor specifically in POMC neurons (POMC-rptor-KO) were treated with an intracerebroventricular (icv) injection of the ROS hydrogen peroxide (H2O2) or the ROS scavenger honokiol, alone or, respectively, in combination with the mTORC1 inhibitor rapamycin or the mTORC1 activator leptin. Oxidant-related signal in POMC neurons was assessed using dihydroethidium (DHE) fluorescence. RESULTS Icv administration of H2O2 decreased food intake, while co-administration of rapamycin, whole-body deletion of S6K1, or deletion of rptor in POMC neurons impeded the anorectic action of H2O2. H2O2 also increased oxidant levels in POMC neurons, an effect that hinged on functional mTORC1 in these neurons. Finally, scavenging ROS prevented the hypophagic action of leptin, which in turn required mTORC1 to increase oxidant levels in POMC neurons and to inhibit food intake. CONCLUSIONS Our results demonstrate that ROS and leptin require mTORC1 pathway activity in POMC neurons to increase oxidant levels in POMC neurons and consequently decrease food intake.
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Affiliation(s)
- Magalie Haissaguerre
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; Department of Endocrinology, Hôpital Haut Lévèque, CHU Bordeaux, F-33600 Pessac, France
| | - Amandine Ferrière
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; Department of Endocrinology, Hôpital Haut Lévèque, CHU Bordeaux, F-33600 Pessac, France
| | - Vincent Simon
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France
| | - Nicolas Saucisse
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France
| | - Nathalie Dupuy
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France
| | - Caroline André
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France
| | - Samantha Clark
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France
| | - Omar Guzman-Quevedo
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France
| | - Antoine Tabarin
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; Department of Endocrinology, Hôpital Haut Lévèque, CHU Bordeaux, F-33600 Pessac, France
| | - Daniela Cota
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000 Bordeaux, France.
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Saneyasu T, Fujita S, Kitashiro A, Fukuzo S, Honda K, Kamisoyama H. Hypothalamic Akt-mediated signaling regulates food intake in chicks. Neurosci Lett 2018; 670:48-52. [DOI: 10.1016/j.neulet.2018.01.032] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Revised: 12/27/2017] [Accepted: 01/17/2018] [Indexed: 10/18/2022]
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